3-Amino-3-arylpropionic acid n-alkyl esters, process for production thereof, and process for production of optically active 3-amino-3-arylpropionic acids and esters of the antipodes thereto

ABSTRACT

The present invention is to provide an n-alkyl 3-amino-3-arylpropionate represented by the formula (I):  
                 
         wherein Ar 1  represents an aryl group which may have a substituent(s), provided that a phenyl group and 4-methoxyphenyl group are excluded, R 1  represents an n-propyl group or an n-butyl group, 
 
and a process for preparing the same, and its optically active compound and an optically active (S or R)-3-amino-3-arylpropionic acid represented by the formula (III-a):  
                 
wherein Ar represents an aryl group which may have a substituent(s), and * represents an asymmetric carbon, 
 
and a process for preparing an optically active n-alkyl (R or S)-3-amino-3-arylpropionate represented by the formula (IV-a):  
                 
   wherein Ar and R 1  have the same meanings as defined above, * represents an asymmetric carbon, provided that it has a reverse absolute configuration to the compound of the formula (III-a).

TECHNICAL FIELD

The present invention relates to a novel n-alkyl3-amino-3-arylpropionate and a process for preparing the same. Then-alkyl 3-amino-3-arylpropionate can be easily led to an opticallyactive 3-amino-3-arylpropionic acid which is useful as a syntheticintermediate of a physiologically active peptide or a lactam seriesantibiotic according to the conventionally known selective hydrolysismethod.

The present invention also relates to a method of obtaining opticallyactive (S or R)-3-amino-3-arylpropionic acid and optically active (R orS)-3-amino-3-arylpropionic acid ester simultaneously from n-alkyl3-amino-3-arylpropionate (racemic mixtures). These3-amino-3-arylpropionic acid and its ester are useful as a startingmaterial or a synthetic intermediate of a physiologically active peptideor a lactam series antibiotic.

BACKGROUND ART

In the prior art, the n-alkyl 3-amino-3-arylpropionate (provided thatthe case where the aryl group is a phenyl group or a 4-methoxyphenylgroup is excluded.) of the present invention is a nove compound, and thepresence thereof and a preparation process have never been known.

Also, as a conventional process for simultaneously obtaining anoptically active (S or R)-3-amino-3-arylpropionic acid and an opticallyactive (R or S)-3-amino-3-arylpropionic acid ester from a3-amino-3-arylpropionic acid ester (racemic mixtures) using hydrolase, aprocess in which an optically active (S)-3-amino-3-arylpropionic acidand an optically active (R)-ethyl 3-amino-3-arylpropionate are obtainedby selectively hydrolyzing one of enantiomers of ethyl3-amino-3-arylpropionate (racemic mixtures) in water in the presence oflipase (tradename: Amano PS) orininated from Burkholderia cepacia(Pseudomonas cepacia) has been disclosed (for example, see TetrahedronLett., 41, 2679 (2000).). However, according to this process, there is aproblem that an E value which is an index of selectivity betweenenantiomers by an enzyme is low. Incidentally, the E value has widelybeen utilized as an index of selectivity of kinetic resolution (forexample, see J. Am. Chem. Soc., 104, 7294 (1982).).

An object of the present invention is to solve the above-mentionedproblems, and to provide a novel n-alkyl 3-amino-3-arylpropionate by asimple and easy process with high yield, and a process for preparing thesame.

Other objects of the present invention is to solve the above-mentionedproblems, and to provide a process for preparing optically active3-amino-3-arylpropionic acid and optically active3-amino-3-arylpropionic acid ester from 3-amino-3-arylpropionic acidester (racemic mixtures), which is industrially suitable and obtainoptically active (S or R)-3-amino-3-arylpropionic acid and opticallyactive (R or S)-3-amino-3-arylpropionic acid ester simultaneously withhigh E values by a simple and easy method.

DISCLOSURE OF THE INVENTION

The present invention relates to an n-alkyl 3-amino-3-arylpropionaterepresented by the formula (I):

wherein Ar¹ represents an aryl group which may have a substituent(s),provided that a phenyl group and a 4-methoxyphenyl group are excluded,R¹ represents an n-propyl group or an n-butyl group.

The present invention also relates to an (R or S)-n-alkyl3-amino-3-arylpropionate represented by the formula (I-a):

wherein Ar¹ and R¹ have the same meanings as defined above, and *represents an asymmetric carbon.

The present invention further relates to a process for preparing ann-alkyl 3-amino-3-arylpropionate represented by the formula (IV):

wherein Ar represents an aryl group which may have a substituent(s),provided that a phenyl gruop is excluded, and R¹ has the same meaningsas defined above,which comprises (A) the first step of reacting an arylaldehyderepresented by the formula (II):

wherein Ar has the same meaning as defined above, malonic acid andammonium acetate in an organic solvent to prepare a3-amino-3-arylpropionic acid represented by the formula (III):

wherein Ar has the same meaning as defined above, (B) the second step ofthen reacting the 3-amino-3-aryl-propionic acid with n-propyl alcohol orn-butyl alcohol in the presence of an acid catalyst.

The present inventors have further studied earnestly to attractedattention to the ester portion of the 3-amino-3-arylpropionic acid ester(racemic mixtures) to be optically resolved, and as a result, they havefound that a substrate in which the ester group is an n-propyl group orn-butyl group alone shows a specifically high E value in the presenthydrolysis reaction.

The present invention further relates to a process for preparing anoptically active (S or R)-3-amino-3-aryl-propionic acid represented bythe formula (III-a):

wherein Ar has the same meaning as defined above,

and * represents an asymmetric carbon, and an optically active (R orS)-n-alkyl 3-amino-3-aryl-propionate represented by the formula (IV-a):

wherein Ar and R¹ has the same meaning as defined above, and *represents an asymmetric carbon, provided that it has a reverse absoluteconfiguretion to that of the compound of the formula (III-a),

which comprises subjecting either one of the enantiomers of the n-alkyl3-amino-3-arylpropionates represented by the above-mentioned formula(IV) which are racemic mixtures to selective hydrolysis reaction in thepresence of a hydrolase in a mixed solvent of an organic solvent and abuffer.

The present invention further relates to a process for preparing anoptically active (S or R)-3-amino-3-aryl-propionic acid and the ester ofthe other enantiomer, which comprises isolating each of the compoundfrom a mixture containing the optically active (S orR)-3-amino-3-aryl-propionic acid represented by the formula (III-a):

wherein Ar has the same meaning as defined above,

and * represents an asymmetric carbon, and the optically active (R orS)-n-alkyl 3-amino-3-arylpropionate represented by the formula (IV-a):

wherein Ar and R¹ have the same meanings as defined above, and *represents an asymmetric carbon, incidentally, it has an oppositeconfiguration to the compound of the formula (III-a),

formed by the above hydrolysis reaction.

BEST MODE FOR CARRYING OUT THE INVENTION

The n-propyl 3-amino-3-arylpropionate in the present invention isrepresented by the above-mentioned formula (I). In the formula (I), Ar¹represents an aryl group which may have a substituent(s) (provided thatphenyl group and 4-methoxyphenyl group are excluded).

The aryl group in the above-mentioned “an aryl group which may have asubstituent(s)” means a substituted phenyl group or naphthyl gruop.Also, the substituent(s) of the aryl group which may have asubstituent(s) may be mentioned an alkyl group having 1 to 4 carbonatoms (Incidentally, these groups contain various kinds of isomers.)such as a methyl group, an ethyl group, a propyl group, a butyl group,etc.; hydroxyl group; a halogen atom such as a chlorine atom, a bromineatom, an iodine atom, a fluorine atom, etc.; an alkoxy group having 2 to4 carbon atoms such as an ethoxy group, etc. (Incidentally, these groupscontain various kinds of isomers.); an alkylenedioxy group having 1 to 4carbon atoms such as a methylenedioxy group, etc.; a nitro group and thelike.

Such “an aryl group which may have a substituent(s)” may be specificallymentioned, for example, a 2-tolyl group, 3-tolyl group, 4-tolyl group,2,3-xylyl group, 2,6-xylyl group, 2,4-xylyl group, 3,4-xylyl group,mesityl group, 2-hydroxyphenyl group, 4-hydroxyphenyl group,3,4-dihydroxyphenyl group, 2-chlorophenyl group, 3-chlorophenyl group,4-chlorophenyl group, 3,4-dichlorophenyl group, 4-bromophenyl group,4-iodophenyl group, 2-fluorophenyl group, 3-fluorophenyl group,4-fluorophenyl group, 3-bromo-5-chloro-2-hydroxyphenyl group,2-methoxyphenyl group, 3-methoxyphenyl group, 3,4-dimethoxyphenyl group,3,4-methylenedioxyphenyl group, 4-ethoxyphenyl group, 4-butoxyphenylgroup, 4-isopropoxyphenyl group, 4-nitrophenyl group, 2-nitrophenylgroup, 1-naphthyl gruop, 2-naphthyl group, etc., preferably a 2-tolylgroup, 4-tolyl group, 2,3-xylyl group, 3,4-xylyl group, 4-hydroxyphenylgroup, 3,4-dihydroxyphenyl group, 2-chlorophenyl group, 4-chlorophenylgroup, 3,4-dichlorophenyl group, 2-fluorophenyl, 3-fluorophenyl group,4-fluorophenyl group, 3-bromo-5-chloro-2-hydroxyphenyl group,2-methoxyphenyl group, 3,4-dimethoxyphenyl group,3,4-methylenedioxyphenyl group, 4-ethoxyphenyl group, 4-nitrophenylgroup, 2-nitrophenyl group, 1-naphthyl gruop, 2-naphthyl gruop, morepreferably 4-tolyl group, 4-hydroxyphenyl group, 3,4-dihydroxyphenylgroup, 4-chlorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group,3,4-dimethoxyphenyl group, 3,4-methylenedioxyphenyl group, 4-nitrophenylgroup, 1-naphthyl gruop, 2-naphthyl gruop.

Also, R¹ represents an n-propyl group or n-butyl group. In the presentinvention, when R¹ is an n-propyl group or n-butyl group, an opticallyactive (S or R)-3-amino-3-arylpropionic acid and an optically active (Ror S)-3-amino-3-arylpropionic acid ester can be simultaneously obtainedwith higher E values.

Specific examples of the n-propyl 3-amino-3-arylpropionate having theabove-mentoined Ar¹, there may be mentioned, for example,

-   n-propyl 3-amino-3-(2-tolyl)propionate,-   n-propyl 3-amino-3-(3-tolyl)propionate,-   n-propyl 3-amino-3-(4-tolyl)propionate,-   n-propyl 3-amino-3-(2,3-xylyl)propionate,-   n-propyl 3-amino-3-(4-ethylphenyl)propionate,-   n-propyl 3-amino-3-(2-chlorophenyl)propionate,-   n-propyl 3-amino-3-(3-chlorophenyl)propionate,-   n-propyl 3-amino-3-(4-chlorophenyl)propionate,-   n-propyl 3-amino-3-(2,3-dichlorophenyl)propionate,-   n-propyl 3-amino-3-(2,4-dichlorophenyl)propionate,-   n-propyl 3-amino-3-(3,4-dichlorophenyl)propionate,-   n-propyl 3-amino-3-(2-bromophenyl)propionate,-   n-propyl 3-amino-3-(3-bromophenyl)propionate,-   n-propyl 3-amino-3-(4-bromophenyl)propionate,-   n-propyl 3-amino-3-(2-fluorophenyl)propionate,-   n-propyl 3-amino-3-(3-fluorophenyl)propionate,-   n-propyl 3-amino-3-(4-fluorophenyl)propionate,-   n-propyl 3-amino-3-(2-iodophenyl)propionate,-   n-propyl 3-amino-3-(3-iodophenyl)propionate,-   n-propyl 3-amino-3-(4-iodophenyl)propionate,-   n-propyl 3-amino-3-(2-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(3-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(4-ethoxyphenyl)propionate,-   n-propyl 3-amino-3-(2-hydroxyphenyl)propionate,-   n-propyl 3-amino-3-(3-hydroxyphenyl)propionate,-   n-propyl 3-amino-3-(4-hydroxyphenyl)propionate,-   n-propyl 3-amino-3-(4-nitrophenyl)propionate,-   n-propyl 3-amino-3-(4-cyanophenyl)propionate,-   n-propyl 3-amino-3-(3,4-dimethoxyphenyl)propionate,-   n-propyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate,-   n-propyl 3-amino-3-(1-phenoxyphenyl)propionate,-   n-propyl 3-amino-3-(4-benzyloxyphenyl)propionate,-   n-propyl 3-amino-3-(1-naphthyl)propionate,-   n-propyl 3-amino-3-(2-naphthyl)propionate,-   n-propyl 3-amino-3-(2-pyridyl)propionate,-   n-propyl 3-amino-3-(3-pyridyl)propionate,-   n-propyl 3-amino-3-(4-pyridyl)propionate,-   n-propyl 3-amino-3-(2-thienyl)propionate,-   n-propyl 3-amino-3-(2-furyl)propionate,-   n-propyl 3-amino-3-(2-quinolyl)propionate and-   n-propyl 3-amino-3-(3-bromo-5-chloro-2-hydroxyphenyl)-propionate-   and the like, preferably-   n-propyl 3-amino-3-(2-tolyl)propionate,-   n-propyl 3-amino-3-(3-tolyl)propionate,-   n-propyl 3-amino-3-(4-tolyl)propionate,-   n-propyl 3-amino-3-(2,3-xylyl)propionate,-   n-propyl 3-amino-3-(2-chlorophenyl)propionate,-   n-propyl 3-amino-3-(3-chlorophenyl)propionate,-   n-propyl 3-amino-3-(4-chlorophenyl)propionate,-   n-propyl 3-amino-3-(3,4-dichlorophenyl)propionate,-   n-propyl 3-amino-3-(2-bromophenyl)propionate,-   n-propyl 3-amino-3-(3-bromophenyl)propionate,-   n-propyl 3-amino-3-(4-bromophenyl)propionate,-   n-propyl 3-amino-3-(2-fluorophenyl)propionate,-   n-propyl 3-amino-3-(3-fluorophenyl)propionate,-   n-propyl 3-amino-3-(4-fluorophenyl)propionate,-   n-propyl 3-amino-3-(2-iodophenyl)propionate,-   n-propyl 3-amino-3-(3-iodophenyl)propionate,-   n-propyl 3-amino-3-(4-iodophenyl)propionate,-   n-propyl 3-amino-3-(2-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(3-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(4-ethoxyphenyl)propionate,-   n-propyl 3-amino-3-(4-hydroxyphenyl)propionate,-   n-propyl 3-amino-3-(4-nitrophenyl)propionate,-   n-propyl 3-amino-3-(4-cyanophenyl)propionate,-   n-propyl 3-amino-3-(3,4-dimethoxyphenyl)propionate,-   n-propyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate,-   n-propyl 3-amino-3-(1-naphthyl)propionate,-   n-propyl 3-amino-3-(2-pyridyl)propionate,-   n-propyl 3-amino-3-(3-pyridyl)propionate and-   n-propyl 3-amino-3-(4-pyridyl)propionate-   and the like, more preferably-   n-propyl 3-amino-3-(2-tolyl)propionate,-   n-propyl 3-amino-3-(3-tolyl)propionate,-   n-propyl 3-amino-3-(4-tolyl)propionate,-   n-propyl 3-amino-3-(2-chlorophenyl)propionate,-   n-propyl 3-amino-3-(3-chlorophenyl)propionate,-   n-propyl 3-amino-3-(4-chlorophenyl)propionate,-   n-propyl 3-amino-3-(3,4-dichlorophenyl)propionate,-   n-propyl 3-amino-3-(2-bromophenyl)propionate,-   n-propyl 3-amino-3-(3-bromophenyl)propionate,-   n-propyl 3-amino-3-(4-bromophenyl)propionate,-   n-propyl 3-amino-3-(2-fluorophenyl)propionate,-   n-propyl 3-amino-3-(3-fluorophenyl)propionate,-   n-propyl 3-amino-3-(4-fluorophenyl)propionate,-   n-propyl 3-amino-3-(4-iodophenyl)propionate,-   n-propyl 3-amino-3-(2-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(3-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(4-hydroxyphenyl)propionate,-   n-propyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate,-   n-propyl 3-amino-3-(3-pyridyl)propionate and-   n-propyl 3-amino-3-(4-pyridyl)propionate-   and the like, particularly preferably-   n-propyl 3-amino-3-(2-tolyl)propionate,-   n-propyl 3-amino-3-(3-tolyl)propionate,-   n-propyl 3-amino-3-(4-tolyl)propionate,-   n-propyl 3-amino-3-(2-chlorophenyl)propionate,-   n-propyl 3-amino-3-(3-chlorophenyl)propionate,-   n-propyl 3-amino-3-(4-chlorophenyl)propionate,-   n-propyl 3-amino-3-(2-bromophenyl)propionate,-   n-propyl 3-amino-3-(3-bromophenyl)propionate,-   n-propyl 3-amino-3-(4-bromophenyl)propionate,-   n-propyl 3-amino-3-(2-fluorophenyl)propionate,-   n-propyl 3-amino-3-(3-fluorophenyl)propionate,-   n-propyl 3-amino-3-(4-fluorophenyl)propionate,-   n-propyl 3-amino-3-(2-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(3-methoxyphenyl)propionate, and-   n-propyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate.

Also, specific examples of the n-butyl 3-amino-3-arylpropionate havingthe above-mentoined Ar¹, there may be mentioned, for example,

-   n-butyl 3-amino-3-(2-tolyl)propionate,-   n-butyl 3-amino-3-(3-tolyl)propionate,-   n-butyl 3-amino-3-(4-tolyl)propionate,-   n-butyl 3-amino-3-(2,3-xylyl)propionate,-   n-butyl 3-amino-3-(2-chlorophenyl)propionate,-   n-butyl 3-amino-3-(3-chlorophenyl)propionate,-   n-butyl 3-amino-3-(4-chlorophenyl)propionate,-   n-butyl 3-amino-3-(2,3-dichlorophenyl)propionate,-   n-butyl 3-amino-3-(2,4-dichlorophenyl)propionate,-   n-butyl 3-amino-3-(3,4-dichlorophenyl)propionate,-   n-butyl 3-amino-3-(3,5-dichlorophenyl)propionate,-   n-butyl 3-amino-3-(2-bromophenyl)propionate,-   n-butyl 3-amino-3-(3-bromophenyl)propionate,-   n-butyl 3-amino-3-(4-bromophenyl)propionate,-   n-butyl 3-amino-3-(2-fluorophenyl)propionate,-   n-butyl 3-amino-3-(3-fluorophenyl)propionate,-   n-butyl 3-amino-3-(4-fluorophenyl)propionate,-   n-butyl 3-amino-3-(3,4-difluorophenyl)propionate,-   n-butyl 3-amino-3-(2-iodophenyl)propionate,-   n-butyl 3-amino-3-(3-iodophenyl)propionate,-   n-butyl 3-amino-3-(4-iodophenyl)propionate,-   n-butyl 3-amino-3-(2-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(3-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(4-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(2,3-dimethoxyphenyl)propionate,-   n-butyl 3-amino-3-(3,4-dimethoxyphenyl)propionate,-   n-butyl 3-amino-3-(3,5-dimethoxyphenyl)propionate and-   n-butyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate-   and the like, preferably-   n-butyl 3-amino-3-(2-tolyl)propionate,-   n-butyl 3-amino-3-(3-tolyl)propionate,-   n-butyl 3-amino-3-(4-tolyl)propionate,-   n-butyl 3-amino-3-(2,3-xylyl)propionate,-   n-butyl 3-amino-3-(2-chlorophenyl)propionate,-   n-butyl 3-amino-3-(3-chlorophenyl)propionate,-   n-butyl 3-amino-3-(4-chlorophenyl)propionate,-   n-butyl 3-amino-3-(3,4-dichlorophenyl)propionate,-   n-butyl 3-amino-3-(2-bromophenyl)propionate,-   n-butyl 3-amino-3-(3-bromophenyl)propionate,-   n-butyl 3-amino-3-(4-bromophenyl)propionate,-   n-butyl 3-amino-3-(2-fluorophenyl)propionate,-   n-butyl 3-amino-3-(3-fluorophenyl)propionate,-   n-butyl 3-amino-3-(4-fluorophenyl)propionate,-   n-butyl 3-amino-3-(2-iodophenyl)propionate,-   n-butyl 3-amino-3-(3-iodophenyl)propionate,-   n-butyl 3-amino-3-(4-iodophenyl)propionate,-   n-butyl 3-amino-3-(2-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(3-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(4-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(2,3-dimethoxyphenyl)propionate and-   n-butyl 3-amino-3- (3, 4-methylenedioxyphenyl)propionate-   and the like, more preferably-   n-butyl 3-amino-3-(2-tolyl)propionate,-   n-butyl 3-amino-3-(3-tolyl)propionate,-   n-butyl 3-amino-3-(4-tolyl)propionate,-   n-butyl 3-amino-3-(2-chlorophenyl)propionate,-   n-butyl 3-amino-3-(3-chlorophenyl)propionate,-   n-butyl 3-amino-3-(4-chlorophenyl)propionate,-   n-butyl 3-amino-3-(3,4-dichlorophenyl)propionate,-   n-butyl 3-amino-3-(2-bromophenyl)propionate,-   n-butyl 3-amino-3-(3-bromophenyl)propionate,-   n-butyl 3-amino-3-(4-bromophenyl)propionate,-   n-butyl 3-amino-3-(2-fluorophenyl)propionate,-   n-butyl 3-amino-3-(3-fluorophenyl)propionate,-   n-butyl 3-amino-3-(4-fluorophenyl)propionate,-   n-butyl 3-amino-3-(4-iodophenyl)propionate,-   n-butyl 3-amino-3-(2-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(3-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(4-methoxyphenyl)propionate and-   n-butyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate-   and the like, particularly preferably-   n-butyl 3-amino-3-(2-tolyl)propionate,-   n-butyl 3-amino-3-(3-tolyl)propionate,-   n-butyl 3-amino-3-(4-tolyl)propionate,-   n-butyl 3-amino-3-(2-chlorophenyl)propionate,-   n-butyl 3-amino-3-(3-chlorophenyl)propionate,-   n-butyl 3-amino-3-(4-chlorophenyl)propionate,-   n-butyl 3-amino-3-(2-bromophenyl)propionate,-   n-butyl 3-amino-3-(3-bromophenyl)propionate,-   n-butyl 3-amino-3-(4-bromophenyl)propionate,-   n-butyl 3-amino-3-(2-fluorophenyl)propionate,-   n-butyl 3-amino-3-(3-fluorophenyl)propionate,-   n-butyl 3-amino-3-(4-fluorophenyl)propionate,-   n-butyl 3-amino-3-(2-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(3-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(4-methoxyphenyl)propionate and-   n-butyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate.

Next, the process for preparing the n-alkyl 3-amino-3-arylpropionaterepresented by the formula (IV-a) according to the present inventionwill be explained.

(A) First Step

The arylaldehyde to be used in the first step of the present inventionis represented by the above-mentioned formula (II). In the formula (II),Ar represents an aryl group which may have a substituent(s).

The aryl group in the above-mentioned “an aryl group which may have asubstituent(s)” is a substituted phenyl group, naphthyl gruop, pyridylgroup, quinolyl group, thienyl group, or furyl group. Also, as thesubstituent(s) in the aryl group which may have a substituent(s), theremay be mentioned an alkyl group having 1 to 4 carbon atoms such asmethyl group, ethyl group, propyl group, butyl group, etc.(incidentally, these groups contain various kinds of isomers.); hydroxylgroup; a halogen atom such as a chlorine atom, a bromine atom, an iodineatom, a fluorine atom, etc.; an alkoxy group having 2 to 4 carbon atomssuch as an ethoxy group, etc. (incidentally, these groups containvarious kinds of isomers.); an alkylenedioxy group having 1 to 4 carbonatoms such as a methylenedioxy group, etc.; nitro group, cyano group,trifluoromethyl group, etc.

Such “an aryl group which may have a substituent(s)” may be specificallymentioned, for example, 2-tolyl group, 3-tolyl group, 4-tolyl group,2,3-xylyl group, 2,6-xylyl group, 2,4-xylyl group, 3,4-xylyl group,mesityl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group,4-hydroxyphenyl group, 2,3-dihydroxyphenyl group, 2,4-dihydroxyphenylgroup, 3,4-dihydroxyphenyl group, 2-chlorophenyl group, 3-chlorophenylgroup, 4-chlorophenyl group, 2,3-dichlorophenyl group,2,4-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenylgroup, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group,2-iodophenyl group, 3-iodophenyl group, 4-iodophenyl group,2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group,2,3-difluorophenyl group, 2,4-difluorophenyl group, 3,4-difluorophenylgroup, 3-bromo-5-chloro-2-hydroxyphenyl group, 2-methoxyphenyl group,3-methoxyphenyl group, 4-methoxyphenyl group, 2,3-dimethoxyphenyl group,2,4-dimethoxyphenyl group, 3,4-dimethoxyphenyl group,3,5-dimethoxyphenyl group, 3,4-methylenedioxyphenyl group,4-ethoxyphenyl group, 4-butoxyphenyl group, 4-isopropoxyphenyl group,1-phenoxyphenyl group, 4-benzyloxyphenyl group, 4-trifluoromethylphenylgroup, 2-nitrophenyl group, 3-nitrophenyl group, 4-nitrophenyl group,4-cyanophenyl group, 4-methoxycarbonylphenyl group, 1-naphthyl gruop,2-naphthyl gruop, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group,3-thienyl group, 3-furyl group, 3-quinolyl group, etc., preferablyphenyl group, 2-tolyl group, 3-tolyl group, 4-tolyl group, 2,3-xylylgroup, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenylgroup, 2,3-dihydroxyphenyl group, 2,4-dihydroxyphenyl group,3,4-dihydroxyphenyl group, 2-chlorophenyl group, 3-chlorophenyl group,4-chlorophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenylgroup, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 2-bromophenylgroup, 3-bromophenyl group, 4-bromophenyl group, 2-iodophenyl group,3-iodophenyl group, 4-iodophenyl group, 2-fluorophenyl group,3-fluorophenyl group, 4-fluorophenyl group, 3,4-difluorophenyl group,3-bromo-5-chloro-2-hydroxyphenyl group, 2-methoxyphenyl group,3-methoxyphenyl group, 4-methoxyphenyl group, 2,3-dimethoxyphenyl group,2,4-dimethoxyphenyl group, 3,4-dimethoxyphenyl group,3,5-dimethoxyphenyl group, 3,4-methylenedioxyphenyl group,4-ethoxyphenyl group, 4-trifluoromethylphenyl group, 4-nitrophenylgroup, 4-cyanophenyl group, 1-naphthyl gruop, 2-naphthyl gruop,2-pyridyl group, 3-pyridyl group, 4-pyridyl group, more preferablyphenyl group, 2-tolyl group, 3-tolyl group, 4-tolyl group, 2,3-xylylgroup, 4-hydroxyphenyl group, 3,4-dihydroxyphenyl group, 2-chlorophenylgroup, 3-chlorophenyl group, 4-chlorophenyl group, 2,3-dichlorophenylgroup, 2,4-dichlorophenyl group, 3,4-dichlorophenyl group,3,5-dichlorophenyl group, 2-bromophenyl group, 3-bromophenyl group,4-bromophenyl group, 4-iodophenyl group, 2-fluorophenyl group,3-fluorophenyl group, 4-fluorophenyl group, 3,4-difluorophenyl group,2-iodophenyl group, 3-iodophenyl group, 4-iodophenyl group,2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group,2,3-dimethoxyphenyl group, 2,4-dimethoxyphenyl group,3,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group,3,4-methylenedioxyphenyl group, 4-trifluoromethylphenyl group,4-nitrophenyl group, 1-naphthyl gruop, 2-naphthyl gruop, 3-pyridylgroup, particularly preferably phenyl group, 2-tolyl group, 3-tolylgroup, 4-tolyl group, 2,3-xylyl group, 2-chlorophenyl group,3-chlorophenyl group, 4-chlorophenyl group, 2,3-dichlorophenyl group,2,4-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenylgroup, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group,2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group,3,4-difluorophenyl group, 2-iodophenyl group, 3-iodophenyl group,4-iodophenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group,4-methoxyphenyl group, 2,3-dimethoxyphenyl group, 3,4-dimethoxyphenylgroup, 3,5-dimethoxyphenyl group or 3,4-methylenedioxyphenyl group.

An amount of the malonic acid to be used in the first step of thepresent invention is preferably 0.5 to 5.0 mol, more preferably 1.0 to1.5 mol based on 1 mol of the arylaldehyde.

An amount of the ammonium acetate to be used in the first step of thepresent invention is preferably 1.0 to 5.0 mol, more preferably 1.0 to3.0 mol based on 1 mol of the arylaldehyde.

As the organic solvent to be used in the first step of the presentinvention, an alcohol solvent and a nitrile solvent are preferred. Thealcohol solvent may be mentioned, for example, methanol, ethanol,n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol,s-butyl alcohol, t-butyl alcohol, etc., preferably methanol, ethanol,isopropyl alcohol, more preferably ethanol, isopropyl alcohol are used.Also, as the nitrile solvent, there may be mentioned, for example,acetonitrile, propionitrile, etc. Incidentally, these the organicsolvents may be used alone or in combination of two or more kinds.

An amount of the above-mentioned organic solvent is optionally adjusteddepending on the uniformity or stirrability of the reaction mixture, andpreferably 1 to 50 mL, more preferably 2 to 10 mL based on 1 g of thearylaldehyde.

The first step of the present invention can be carried out, for example,under nitrogen atmosphere, by the method of mixing an arylaldehyde,malonic acid, ammonium acetate and an alcoholic solvent, and reactingthe same while stirring, and the like. The reaction temperature at thetime is preferably 40 to 150° C., more preferably 50 to 100° C., and thereaction pressure is not specifically limited.

The 3-amino-3-arylpropionic acid obtained by the first step of thepresent invention is isolated and purified by, after completion of thereaction, a general method such as filtration, extraction,concentration, recrystallization, crystallization, columnchromatography, etc., and then, used in the next second step.

(B) Second Step

As the acid catalyst to be used in the second step of the presentinvention, there may be mentioned, for example, hydrochloric acid,sulfuric acid, phosphoric acid, nitric acid, p-toluenesulfonic acid,etc., preferably hydrochloric acid, sulfuric acid, p-toluenesulfonicacid, more preferably hydrochloric acid, sulfuric acid are used.Incidentally, these acids may be used alone or in combination of two ormore kinds in admixture.

An amount of the above-mentioned acid catalyst to be used is preferably0.1 to 20 mol, more preferably 1.0 to 5.0 mol based on 1 mol of3-amino-3-arylpropionic acid.

An amount of the above-mentioned n-propyl alcohol or n-butyl alcohol tobe used is preferably 1 to 100 mol, more preferably 5 to 40 mol based on1 mol of 3-amino-3-arylpropionic acid.

The second step of the present invention can be carried out, forexample, by a method in which 3-amino-3-arylpropionic acid and n-propylalcohol or n-butyl alcohol are mixed under nitrogen atmosphere, andthese materials were reacted under stirring, and the like. The reactiontemperature at the time is preferably 40 to 100° C., more preferably 50to 70° C., and the reaction pressure is not specifically limited.

The 3-amino-3-arylpropionic acid n-propyl ester or n-butyl esterobtained by the second step of the present invention can be isolated andpurified by a conventional method, for example, such as filtration,extraction, concentration, recrystallization, crystallization, columnchromatography, etc. after completion of the reaction.

Next, a hydrolysis reaction of n-alkyl 3-amino-3-arylpropionaterepresented by the formula (IV-a) of the present invention is explained.In this hydrolysis reaction, for example, as shown by the followingformula (V):

wherein Ar, R¹ and * have the same meanings as defined above,

only one enantiomer of the racemic mixtures of n-alkyl3-amino-3-arylpropionate (hereinafter sometimes referred to as Compound(IV-a).) represented by the above-mentioned formula (IV-a) isselectively hydrolyzed in the presence of a hydrolase, to form anoptically active (S or R)-3-amino-3-arylpropionic acid (hereinaftersometimes referred to as Compound (III-a).) represented by the formula(III-a), and simultaneously to obtain an unreacted optically active (Ror S)-n-alkyl 3-amino-3-arylpropionate (hereinafter sometimes referredto as Compound (IV-a).) represented by the formula (IV-a). Incidentally,Compound (III-a) and Compound (IV-a) have the reverse absoluteconfiguration to each other.

Ar of Compound (IV) is as mentioned above.

Compound (IV) to be used in the hydrolysis reaction of the presentinvention can be prepared by, for example, reacting an aldehydecompound, malonic acid and ammonium acetate, and then, further reactingn-propyl alcohol or n-butyl alcohol in the presence of an acid catalyst.

Specific examples of the n-propyl ester of Compound (IV) having theabove-mentioned Ar may be mentioned, for example,

-   n-propyl 3-amino-3-phenylpropionate,-   n-propyl 3-amino-3-(2-tolyl)propionate,-   n-propyl 3-amino-3-(3-tolyl)propionate,-   n-propyl 3-amino-3-(4-tolyl)propionate,-   n-propyl 3-amino-3-(2,3-xylyl)propionate,-   n-propyl 3-amino-3-(4-ethylphenyl)propionate,-   n-propyl 3-amino-3-(2-chlorophenyl)propionate,-   n-propyl 3-amino-3-(3-chlorophenyl)propionate,-   n-propyl 3-amino-3-(4-chlorophenyl)propionate,-   n-propyl 3-amino-3-(2,3-dichlorophenyl)propionate,-   n-propyl 3-amino-3-(2,4-dichlorophenyl)propionate,-   n-propyl 3-amino-3-(3,4-dichlorophenyl)propionate,-   n-propyl 3-amino-3-(2-bromophenyl)propionate,-   n-propyl 3-amino-3-(3-bromophenyl)propionate,-   n-propyl 3-amino-3-(4-bromophenyl)propionate,-   n-propyl 3-amino-3-(2-fluorophenyl)propionate,-   n-propyl 3-amino-3-(3-fluorophenyl)propionate,-   n-propyl 3-amino-3-(4-fluorophenyl)propionate,-   n-propyl 3-amino-3-(2-iodophenyl)propionate,-   n-propyl 3-amino-3-(3-iodophenyl)propionate,-   n-propyl 3-amino-3-(4-iodophenyl)propionate,-   n-propyl 3-amino-3-(2-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(3-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(4-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(4-ethoxyphenyl)propionate,-   n-propyl 3-amino-3-(2-hydroxyphenyl)propionate,-   n-propyl 3-amino-3-(3-hydroxyphenyl)propionate,-   n-propyl 3-amino-3-(4-hydroxyphenyl)propionate,-   n-propyl 3-amino-3-(4-nitrophenyl)propionate,-   n-propyl 3-amino-3-(4-cyanophenyl)propionate,-   n-propyl 3-amino-3-(3,4-dimethoxyphenyl)propionate,-   n-propyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate,-   n-propyl 3-amino-3-(1-phenoxyphenyl)propionate,-   n-propyl 3-amino-3-(4-benzyloxyphenyl)propionate,-   n-propyl 3-amino-3-(1-naphthyl)propionate,-   n-propyl 3-amino-3-(2-naphthyl)propionate,-   n-propyl 3-amino-3-(2-pyridyl)propionate,-   n-propyl 3-amino-3-(3-pyridyl)propionate,-   n-propyl 3-amino-3-(4-pyridyl)propionate,-   n-propyl 3-amino-3-(2-thienyl)propionate,-   n-propyl 3-amino-3-(2-furyl)propionate,-   n-propyl 3-amino-3-(2-quinolyl)propionate and-   n-propyl 3-amino-3-(3-bromo-5-chloro-2-hydroxyphenyl)propionate,-   and the like, preferably-   n-propyl 3-amino-3-phenylpropionate,-   n-propyl 3-amino-3-(2-tolyl)propionate,-   n-propyl 3-amino-3-(3-tolyl)propionate,-   n-propyl 3-amino-3-(4-tolyl)propionate,-   n-propyl 3-amino-3-(2,3-xylyl)propionate,-   n-propyl 3-amino-3-(2-chlorophenyl)propionate,-   n-propyl 3-amino-3-(3-chlorophenyl)propionate,-   n-propyl 3-amino-3-(4-chlorophenyl)propionate,-   n-propyl 3-amino-3-(3,4-dichlorophenyl)propionate,-   n-propyl 3-amino-3-(2-bromophenyl)propionate,-   n-propyl 3-amino-3-(3-bromophenyl)propionate,-   n-propyl 3-amino-3-(4-bromophenyl)propionate,-   n-propyl 3-amino-3-(2-fluorophenyl)propionate,-   n-propyl 3-amino-3-(3-fluorophenyl)propionate,-   n-propyl 3-amino-3-(4-fluorophenyl)propionate,-   n-propyl 3-amino-3-(2-iodophenyl)propionate,-   n-propyl 3-amino-3-(3-iodophenyl)propionate,-   n-propyl 3-amino-3-(4-iodophenyl)propionate,-   n-propyl 3-amino-3-(2-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(3-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(4-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(4-ethoxyphenyl)propionate,-   n-propyl 3-amino-3-(4-hydroxyphenyl)propionate,-   n-propyl 3-amino-3-(4-nitrophenyl)propionate,-   n-propyl 3-amino-3-(4-cyanophenyl)propionate,-   n-propyl 3-amino-3-(3,4-dimethoxyphenyl)propionate,-   n-propyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate,-   n-propyl 3-amino-3-(1-naphthyl)propionate,-   n-propyl 3-amino-3-(2-pyridyl)propionate,-   n-propyl 3-amino-3-(3-pyridyl)propionate and-   n-propyl 3-amino-3-(4-pyridyl)propionate,-   and the like, more preferably-   n-propyl 3-amino-3-phenylpropionate,-   n-propyl 3-amino-3-(2-tolyl)propionate,-   n-propyl 3-amino-3-(3-tolyl)propionate,-   n-propyl 3-amino-3-(4-tolyl)propionate,-   n-propyl 3-amino-3-(2-chlorophenyl)propionate,-   n-propyl 3-amino-3-(3-chlorophenyl)propionate,-   n-propyl 3-amino-3-(4-chlorophenyl)propionate,-   n-propyl 3-amino-3-(3,4-dichlorophenyl)propionate,-   n-propyl 3-amino-3-(2-bromophenyl)propionate,-   n-propyl 3-amino-3-(3-bromophenyl)propionate,-   n-propyl 3-amino-3-(4-bromophenyl)propionate,-   n-propyl 3-amino-3-(2-fluorophenyl)propionate,-   n-propyl 3-amino-3-(3-fluorophenyl)propionate,-   n-propyl 3-amino-3-(4-fluorophenyl)propionate,-   n-propyl 3-amino-3-(4-iodophenyl)propionate,-   n-propyl 3-amino-3-(2-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(3-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(4-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(4-hydroxyphenyl)propionate,-   n-propyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate,-   n-propyl 3-amino-3-(3-pyridyl)propionate and-   n-propyl 3-amino-3-(4-pyridyl)propionate,-   and the like, particularly preferably-   n-propyl 3-amino-3-phenylpropionate,-   n-propyl 3-amino-3-(2-tolyl)propionate,-   n-propyl 3-amino-3-(3-tolyl)propionate,-   n-propyl 3-amino-3-(4-tolyl)propionate,-   n-propyl 3-amino-3-(2-chlorophenyl)propionate,-   n-propyl 3-amino-3-(3-chlorophenyl)propionate,-   n-propyl 3-amino-3-(4-chlorophenyl)propionate,-   n-propyl 3-amino-3-(2-bromophenyl)propionate,-   n-propyl 3-amino-3-(3-bromophenyl)propionate,-   n-propyl 3-amino-3-(4-bromophenyl)propionate,-   n-propyl 3-amino-3-(2-fluorophenyl)propionate,-   n-propyl 3-amino-3-(3-fluorophenyl)propionate,-   n-propyl 3-amino-3-(4-fluorophenyl)propionate,-   n-propyl 3-amino-3-(2-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(3-methoxyphenyl)propionate,-   n-propyl 3-amino-3-(4-methoxyphenyl)propionate and-   n-propyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate.

Also, specific examples of an n-butyl ester of Compound (IV) having theabove-mentioned Ar may be mentioned, for example,

-   n-butyl 3-amino-3-phenylpropionate,-   n-butyl 3-amino-3-(2-tolyl)propionate,-   n-butyl 3-amino-3-(3-tolyl)propionate,-   n-butyl 3-amino-3-(4-tolyl)propionate,-   n-butyl 3-amino-3-(2,3-xylyl)propionate,-   n-butyl 3-amino-3-(2-chlorophenyl)propionate,-   n-butyl 3-amino-3-(3-chlorophenyl)propionate,-   n-butyl 3-amino-3-(4-chlorophenyl)propionate,-   n-butyl 3-amino-3-(2,3-dichlorophenyl)propionate,-   n-butyl 3-amino-3-(2,4-dichlorophenyl)propionate,-   n-butyl 3-amino-3-(3,4-dichlorophenyl)propionate,-   n-butyl 3-amino-3-(3,5-dichlorophenyl)propionate,-   n-butyl 3-amino-3-(2-bromophenyl)propionate,-   n-butyl 3-amino-3-(3-bromophenyl)propionate,-   n-butyl 3-amino-3-(4-bromophenyl)propionate,-   n-butyl 3-amino-3-(2-fluorophenyl)propionate,-   n-butyl 3-amino-3-(3-fluorophenyl)propionate,-   n-butyl 3-amino-3-(4-fluorophenyl)propionate,-   n-butyl 3-amino-3-(3,4-difluorophenyl)propionate,-   n-butyl 3-amino-3-(2-iodophenyl)propionate,-   n-butyl 3-amino-3-(3-iodophenyl)propionate,-   n-butyl 3-amino-3-(4-iodophenyl)propionate,-   n-butyl 3-amino-3-(2-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(3-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(4-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(2,3-dimethoxyphenyl)propionate,-   n-butyl 3-amino-3-(3,4-dimethoxyphenyl)propionate,-   n-butyl 3-amino-3-(3,5-dimethoxyphenyl)propionate and-   n-butyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate,-   and the like, preferably-   n-butyl 3-amino-3-phenylpropionate,-   n-butyl 3-amino-3-(2-tolyl)propionate,-   n-butyl 3-amino-3-(3-tolyl)propionate,-   n-butyl 3-amino-3-(4-tolyl)propionate,-   n-butyl 3-amino-3-(2,3-xylyl)propionate,-   n-butyl 3-amino-3-(2-chlorophenyl)propionate,-   n-butyl 3-amino-3-(3-chlorophenyl)propionate,-   n-butyl 3-amino-3-(4-chlorophenyl)propionate,-   n-butyl 3-amino-3-(3,4-dichlorophenyl)propionate,-   n-butyl 3-amino-3-(2-bromophenyl)propionate,-   n-butyl 3-amino-3-(3-bromophenyl)propionate,-   n-butyl 3-amino-3-(4-bromophenyl)propionate,-   n-butyl 3-amino-3-(2-fluorophenyl)propionate,-   n-butyl 3-amino-3-(3-fluorophenyl)propionate,-   n-butyl 3-amino-3-(4-fluorophenyl)propionate,-   n-butyl 3-amino-3-(2-iodophenyl)propionate,-   n-butyl 3-amino-3-(3-iodophenyl)propionate,-   n-butyl 3-amino-3-(4-iodophenyl)propionate,-   n-butyl 3-amino-3-(2-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(3-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(4-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(2,3-dimethoxyphenyl)propionate and-   n-butyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate,-   and the like, more preferably-   n-butyl 3-amino-3-phenylpropionate,-   n-butyl 3-amino-3-(2-tolyl)propionate,-   n-butyl 3-amino-3-(3-tolyl)propionate,-   n-butyl 3-amino-3-(4-tolyl)propionate,-   n-butyl 3-amino-3-(2-chlorophenyl)propionate,-   n-butyl 3-amino-3-(3-chlorophenyl)propionate,-   n-butyl 3-amino-3-(4-chlorophenyl)propionate,-   n-butyl 3-amino-3-(3,4-dichlorophenyl)propionate,-   n-butyl 3-amino-3-(2-bromophenyl)propionate,-   n-butyl 3-amino-3-(3-bromophenyl)propionate,-   n-butyl 3-amino-3-(4-bromophenyl)propionate,-   n-butyl 3-amino-3-(2-fluorophenyl)propionate,-   n-butyl 3-amino-3-(3-fluorophenyl)propionate,-   n-butyl 3-amino-3-(4-fluorophenyl)propionate,-   n-butyl 3-amino-3-(4-iodophenyl)propionate,-   n-butyl 3-amino-3-(2-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(3-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(4-methoxyphenyl)propionate and-   n-butyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate,-   and the like, particularly preferably-   n-butyl 3-amino-3-phenylpropionate,-   n-butyl 3-amino-3-(2-tolyl)propionate,-   n-butyl 3-amino-3-(3-tolyl)propionate,-   n-butyl 3-amino-3-(4-tolyl)propionate,-   n-butyl 3-amino-3-(2-chlorophenyl)propionate,-   n-butyl 3-amino-3-(3-chlorophenyl)propionate,-   n-butyl 3-amino-3-(4-chlorophenyl)propionate,-   n-butyl 3-amino-3-(2-bromophenyl)propionate,-   n-butyl 3-amino-3-(3-bromophenyl)propionate,-   n-butyl 3-amino-3-(4-bromophenyl)propionate,-   n-butyl 3-amino-3-(2-fluorophenyl)propionate,-   n-butyl 3-amino-3-(3-fluorophenyl)propionate,-   n-butyl 3-amino-3-(4-fluorophenyl)propionate,-   n-butyl 3-amino-3-(2-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(3-methoxyphenyl)propionate,-   n-butyl 3-amino-3-(4-methoxyphenyl)propionate and-   n-butyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate.

As the hydrolase to be used in the hydrolysis of the present invention,there may be mentioned, for example, protease, esterase, lipase, etc.,preferably lipase of microorganism which can be isolated from yeast orbacteria, more preferably lipase (for example, Amano PS (available fromAmano Enzyme Co.), etc.) originated from Burkholderia cepacia(Pseudomonas cepacia) may be used. Incidentally, as these hydrolases, acommercially available product can be used in a natural form or a fixedenzyme as such, and they may be used singly or in admixture of two ormore kinds. Also, an enzyme-fixing agent to be contained in acommercially available product may be previously removed and then used.

An amount of the above-mentioned hydrolase is preferably 0.1 to 1000 mg,more preferably 1 to 200 mg based on 1 g of Compound (IV-a).

Hydrolysis reaction of the present invention can be carried out in amixed solvent of an organic solvent and a buffer.

In the hydrolysis reaction of the present invention, water may be added.As the water, purified water such as deionized water, distilled water,etc. is preferably used. Incidentally, when water is used as thesolvent, weak base such as potassium hydrogen carbonate, sodium hydrogencarbonate, etc. may be present in the reaction system to neutralize theformed Compound (III-a). An amount of the above-mentioned weak base ispreferably 0.5 to 1.0 mol based on 1 mol of Compound (III-a).

As the above-mentioned buffer, there may be mentioned, for example, anaqueous solution of an inorganic acid salt such as an aqueous sodiumphosphate solution, an aqueous potassium phosphate solution, etc.; anaqueous solution of an organic acid salt such as an aqueous sodiumacetate solution, an aqueous ammonium acetate solution, an aqueoussodium citrate solution, etc., preferably an aqueous solution of aninorganic acid salt, more preferably an aqueous sodium phosphatesolution, an aqueous potassium phosphate solution, an aqueous ammoniumacetate solution is/are used. These buffers may be used used singly orin admixture of two or more kinds.

A concentration of the buffer is preferably 0.01 to 2 mol/L, morepreferably 0.05 to 0.5 mol/L, and a pH of the buffer is preferably 4 to9, more preferably 7 to 8.5.

As the above-mentioned organic solvent, there may be mentioned, forexample, aliphatic hydrocarbons such as n-pentane, n-hexane, n-heptane,n-octane, cyclopentane, cyclohexane, cyclopentane, etc.; aromatichydrocarbons such as benzene, toluene, xylene, etc.; ethers such asdiethyl ether, t-butyl methyl ether, diisopropyl ether, tetrahydrofuran,1,4-dioxane, etc., preferably n-hexane, n-heptane, cyclopentane,cyclohexane, toluene, diisopropyl ether, t-butyl methyl ether,tetrahydrofuran, more preferably n-hexane, cyclohexane, toluene,diisopropyl ether, t-butyl methyl ether, particularly preferablycyclohexane, toluene, t-butyl methyl ether is/are used.

An amount of the solvent (a mixed solvent of the organic solvent and thebuffer) to be used in the hydrolysis reaction of the present inventionis preferably 2 to 200 mL, more preferably 5 to 80 mL based on 1 g ofCompound (IV-a).

In the hydrolysis reaction of the present invention, an amount of theorganic solvent to be used when the mixed solvent of the organic solventand the buffer is used as a solvent is preferably 0.1 to 10 mL, morepreferably 0.5 to 5 mL based on 1 mL of the buffer.

The hydrolysis reaction of the present invention can be carried out, forexample, by a method in which Compound (IV-a), the hydrolase and thesolvent (a mixed solvent of the organic solvent and the buffer) aremixed and reacted while stirring, and the like. A reaction temperatureat that time is preferably 0 to 80° C., more preferably 10 to 50° C.,particularly preferably 30 to 45° C., and a reaction pressure is notspecifically limited.

From Compound (III-a) and Compound (IV-a) obtained by the hydrolysisreaction of the present invention, for example, after completion of thereaction, Compound (III-a) can be obtained by adding a suitable organicsolvent (for example, acetonitrile, acetone, etc.) to the reactionmixture and then filtering the same, and Compound (IV-a) can be alsoobtained by controlling a pH of the filtrate, and then concentrating theorganic layer. Also, filtration or addition of sodium chloride beforeobtaining the desired compound may be carried out to improve a recoveryrate of Compound (III-a). Incidentally, these compounds may be furtherpurified by a conventional manner such as crystallization,recrystallization, distillation, column chromatography, etc.

Also, Compound (III-a) can be converted into a corresponding opticallyactive 3-amino-3-arylpropionic acid n-propyl ester or n-butyl ester byreacting with n-propyl alcohol or n-butyl alcohol in the presence of anacid catalyst according to the above-mentioned method.

Specific examples of Compound (III-a) obtained by the hydrolysisreaction of the present invention may be mentioned, for example,

-   optically active (S or R)-3-amino-3-phenylpropionic acid,-   optically active (S or R)-3-amino-3-(2-tolyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-tolyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-tolyl)propionic acid,-   optically active (S or R)-3-amino-3-(2,3-xylyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-ethylphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-chlorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-chlorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-chlorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(2,3-dichlorophenyl)propionic    acid,-   optically active (S or R)-3-amino-3-(2,4-dichlorophenyl)propionic    acid,-   optically active (S or R)-3-amino-3-(3,4-dichlorophenyl)propionic    acid,-   optically active (S or R)-3-amino-3-(2-bromophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-bromophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-bromophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-fluorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-fluorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-fluorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-iodophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-iodophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-iodophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-methoxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-methoxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-methoxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-ethoxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-hydroxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-hydroxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-hydroxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-nitrophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-cyanophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3,4-dimethoxyphenyl)propionic    acid,-   optically active (S or    R)-3-amino-3-(3,4-methylenedioxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(1-phenoxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-benzyloxyphenyl)propionic    acid,-   optically active (S or R)-3-amino-3-(1-naphthyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-naphthyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-pyridyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-pyridyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-pyridyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-thienyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-furyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-quinolyl)propionic acid and-   optically active (S or    R)-3-amino-3-(3-bromo-5-chloro-2-hydroxyphenyl)propionic acid,-   and the like, preferably-   optically active (S or R)-3-amino-3-phenylpropionic acid,-   optically active (S or R)-3-amino-3-(2-tolyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-tolyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-tolyl)propionic acid,-   optically active (S or R)-3-amino-3-(2,3-xylyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-ethylphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-chlorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-chlorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-chlorophenyl)propionic acid,-   optically active (S or R)-3-3-amino-3-(3,4-dichlorophenyl)propionic    acid,-   optically active (S or R)-3-amino-3-(2-bromophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-bromophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-bromophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-fluorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-fluorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-fluorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-iodophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-iodophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-iodophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-methoxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-methoxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-methoxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-ethoxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-hydroxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-nitrophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-cyanophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3,4-dimethoxyphenyl)propionic    acid,-   optically active (S or    R)-3-amino-3-(3,4-methylenedioxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(1-naphthyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-pyridyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-pyridyl)propionic acid and-   optically active (S or R)-3-amino-3-(4-pyridyl)propionic acid,-   and the like, more preferably-   optically active (S or R)-3-amino-3-phenylpropionic acid,-   optically active (S or R)-3-amino-3-(2-tolyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-tolyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-tolyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-chlorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-chlorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-chlorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3,4-dichlorophenyl)propionic    acid,-   optically active (S or R)-3-amino-3-(2-bromophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-bromophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-bromophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-fluorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-fluorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-fluorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-iodophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-methoxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-methoxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-methoxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-hydroxyphenyl)propionic acid,-   optically active (S or    R)-3-amino-3-(3,4-methylenedioxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-pyridyl)propionic acid and-   optically active (S or R)-3-amino-3-(4-pyridyl)propionic acid,-   and the like, particularly preferably-   optically active (S or R)-3-amino-3-phenylpropionic acid,-   optically active (S or R)-3-amino-3-(2-tolyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-tolyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-tolyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-chlorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-chlorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-chlorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-bromophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-bromophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-bromophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-fluorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-fluorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-fluorophenyl)propionic acid,-   optically active (S or R)-3-amino-3-(2-methoxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(3-methoxyphenyl)propionic acid,-   optically active (S or R)-3-amino-3-(4-methoxyphenyl)propionic acid    and-   optically active (S or    R)-3-amino-3-(3,4-methylenedioxyphenyl)propionic acid.

Specific examples of the n-propyl ester of the unreacted Compound (IV-a)(which has a reverse absolute configuration to that of Compound(III-a).) which did not reacted in the hydrolysis reaction of thepresent invention may be mentioned, for example,

-   optically active (R or S)-n-propyl 3-amino-3-phenylpropionate,-   optically active (R or S)-n-propyl 3-amino-3-(2-tolyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(3-tolyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(4-tolyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(2,3-xylyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-ethylphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-chlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-chlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-chlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2,3-dichlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2,4-dichlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3,4-dichlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-bromophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-bromophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-bromophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-fluorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-fluorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-fluorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-iodophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-iodophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-iodophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-methoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-methoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-methoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-ethoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-hydroxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-hydroxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-hydroxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-nitrophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-cyanophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3,4-dimethoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3,4-methylenedioxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(1-phenoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-benzyloxyphenyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(1-naphthyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(2-pyridyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(3-pyridyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(4-pyridyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(2-thienyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(2-furyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(2-quinolyl)propionate    and-   optically active (R or S)-n-propyl    3-amino-3-(3-bromo-5-chloro-2-hydroxyphenyl)propionate-   and the like, preferably-   optically active (R or S)-n-propyl 3-amino-3-phenylpropionate,-   optically active (R or S)-n-propyl 3-amino-3-(2-tolyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(3-tolyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(4-tolyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(2,3-xylyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-chlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-chlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-chlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3,4-dichlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-bromophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-bromophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-bromophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-fluorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-fluorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-fluorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-iodophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-iodophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-iodophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-methoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-methoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-methoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-ethoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-hydroxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-nitrophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-cyanophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3,4-dimethoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3,4-methylenedioxyphenyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(1-naphthyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(2-pyridyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(3-pyridyl)propionate    and-   optically active (R or S)-n-propyl 3-amino-3-(4-pyridyl)propionate,-   and the like, more preferably-   optically active (R or S)-n-propyl 3-amino-3-phenylpropionate,-   optically active (R or S)-n-propyl 3-amino-3-(2-tolyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(3-tolyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(4-tolyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-chlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-chlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-chlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3,4-dichlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-bromophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-bromophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-bromophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-fluorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-fluorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-fluorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-iodophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-methoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-methoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-methoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-ethoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-hydroxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3,4-methylenedioxyphenyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(3-pyridyl)propionate    and-   optically active (R or S)-n-propyl 3-amino-3-(4-pyridyl)propionate,-   and the like, particularly preferably-   optically active (R or S)-n-propyl 3-amino-3-phenylpropionate,-   optically active (R or S)-n-propyl 3-amino-3-(2-tolyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(3-tolyl)propionate,-   optically active (R or S)-n-propyl 3-amino-3-(4-tolyl)propionate-   optically active (R or S)-n-propyl    3-amino-3-(2-chlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-chlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-chlorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-bromophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-bromophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-bromophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-fluorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-fluorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-fluorophenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(2-methoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(3-methoxyphenyl)propionate,-   optically active (R or S)-n-propyl    3-amino-3-(4-methoxyphenyl)propionate and-   optically active (R or S)-n-propyl    3-amino-3-(3,4-methylenedioxyphenyl)propionate.

Also, specific examples of the n-butyl ester of Compound (IV-a) obtainedby the hydrolysis reaction of the present invention may be mentioned,for example,

-   optically active (R or S)-n-butyl 3-amino-3-(2-tolyl)propionate,-   optically active (R or S)-n-butyl 3-amino-3-(3-tolyl)propionate,-   optically active (R or S)-n-butyl 3-amino-3-(4-tolyl)propionate,-   optically active (R or S)-n-butyl 3-amino-3-(2,3-xylyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-chlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-chlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-chlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2,3-dichlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2,4-dichlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3,4-dichlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3,5-dichlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-bromophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-bromophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-bromophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-fluorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-fluorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-fluorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3,4-difluorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-iodophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-iodophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-iodophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-methoxyphenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-methoxyphenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-methoxyphenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2,3-dimethoxyphenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3,4-dimethoxyphenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3,5-dimethoxyphenyl)propionate and-   optically active (R or S)-n-butyl    3-amino-3-(3,4-methylenedioxyphenyl)propionate,-   and the like, preferably-   optically active (R or S)-n-butyl 3-amino-3-(2-tolyl)propionate,-   optically active (R or S)-n-butyl 3-amino-3-(3-tolyl)propionate,-   optically active (R or S)-n-butyl 3-amino-3-(4-tolyl)propionate,-   optically active (R or S)-n-butyl 3-amino-3-(2,3-xylyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-chlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-chlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-chlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3,4-dichlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-bromophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-bromophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-bromophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-fluorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-fluorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-fluorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-iodophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-iodophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-iodophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-methoxyphenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-methoxyphenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-methoxyphenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3,4-dimethoxyphenyl)propionate and-   optically active (R or S)-n-butyl    3-amino-3-(3,4-methylenedioxyphenyl)propionate,-   and the like, more preferably-   optically active (R or S)-n-butyl 3-amino-3-(2-tolyl)propionate,-   optically active (R or S)-n-butyl 3-amino-3-(3-tolyl)propionate,-   optically active (R or S)-n-butyl 3-amino-3-(4-tolyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-chlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-chlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-chlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3,4-dichlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-bromophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-bromophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-bromophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-fluorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-fluorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-fluorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-iodophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-methoxyphenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-methoxyphenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-methoxyphenyl)propionate and-   optically active (R or S)-n-butyl    3-amino-3-(3,4-methylenedioxyphenyl)propionate,-   and the like, particularly preferably-   optically active (R or S)-n-butyl 3-amino-3-(2-tolyl)propionate,-   optically active (R or S)-n-butyl 3-amino-3-(3-tolyl)propionate,-   optically active (R or S)-n-butyl 3-amino-3-(4-tolyl)propionate-   optically active (R or S)-n-butyl    3-amino-3-(2-chlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-chlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-chlorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-bromophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-bromophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-bromophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-fluorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-fluorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-fluorophenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(2-methoxyphenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(3-methoxyphenyl)propionate,-   optically active (R or S)-n-butyl    3-amino-3-(4-methoxyphenyl)propionate and-   optically active (R or S)-n-butyl    3-amino-3-(3,4-methylenedioxyphenyl)propionate.

EXAMPLE

Next, the present invention is explained more specifically by referringto Examples, but the scope of the present invention is not limited bythese.

Reference Example 1 Synthesis of 3-amino-3-phenylpropionic acid (RacemicMixtures)

To 250 mL of isopropyl alcohol were added 17.7 g (0.17 mol) ofbenzaldehyde, 18.2 g (0.17 mol) of malonic acid and 25.6 g (0.33 mol) ofammonium acetate, and the mixture was reacted while stirring and underreflux (80 to 90° C.) for 7 hours. After completion of the reaction, theobtained reaction mixture was stirred at 0 to 5° C. for 1 hour and thenfiltered to give 19.2 g of 3-amino-3-phenylpropionic acid (racemicmixtures) (isolation yield based on benzaldehyde: 70.0%) as whitepowder.

Incidentally, physical properties of the 3-amino-3-phenylpropionic acid(racemic mixtures) were as follows.

¹H-NMR (δ (ppm), D₂O+DCl): 3.06 (dd, 1H, J=17.1, 6.8 Hz), 3.17 (dd, 1H,J=17.1, 7.3 Hz), 4.76 (dd, 1H, J=7.3, 6.8 Hz), 3.77 (s, 2H), 7.45 (m,5H)

¹³C-NMR (δ (ppm), D₂O+DCl): 40.5, 54.4, 130.0, 132.3, 132.6, 138.0,176.3

MS (EI) m/z: 165 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 166 (MH⁺)

Elemental analysis; Calcd: C, 65.44%; H, 6.71%; N, 8.48% Found: C,65.18%; H, 6.78%; N, 8.34%

Reference example 2 Synthesis of n-propyl 3-amino-3-phenylpropionate(Racemic Mixtures)

To 6.00 mL (120 mmol) of n-propyl alcohol were added 2.00 g (12.1 mmol)of 3-amino-3-phenylpropionic acid (racemic mixtures) synthesized inReference example 1 and 1.78 g (18.2 mmol) of conc. sulfuric acid, andthe mixture was reacted while stirring at 60° C. for 4 hours. Aftercompletion of the reaction, the obtained reaction mixture wasconcentrated under reduced pressure, then, 6 mol/L aqueous sodiumhydroxide solution was added thereto to adjust a pH of the reactionmixture to 8.5. Then, 10 mL of ethyl acetate and 4 mL of water wereadded to the mixture to carry out extraction, and the organic layer wasdried over anhydrous magnesium sulfate. After filtration, the filtratewas concentrated under reduced pressure to give 2.16 g of n-propyl3-amino-3-phenylpropionate (racemic mixtures) (isolation yield based on3-amino-3-phenylpropionic acid (racemic mixtures): 86.1%) as colorlessliquid.

Incidentally, physical properties of the n-propyl3-amino-3-phenylpropionate (racemic mixtures) were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.90 (d, 3H, J=7.3 Hz), 1.55-1.65 (tq, 2H,J=7.3, 6.8 Hz), 2.63 (d, 2H, J=6.8 Hz), 4.01 (t, 2H, J=6.8 Hz), 4.39 (d,1H, J=6.8 Hz), 7.20-7.35 (m, 5H)

¹³C-NMR (δ (ppm), CDCl₃): 10.4, 21.9, 44.2, 52.7, 66.1, 126.2, 127.3,128.6, 144.7, 172.0

MS (EI) m/z: 207 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 208 (MH⁺)

Elemental analysis; Calcd: C, 69.54%; H, 8.27%; N, 6.76% Found: C,68.86%; H, 8.22%; N, 6.60%

Example 1 Syntheses of (S)-3-amino-3-phenylpropionic acid and(R)-n-propyl 3-amino-3-phenylpropionate)

To a mixed solution comprising 4.75 mL of 50 mmol/L aqueous potassiumphosphate solution with a pH of 8.2 and 0.25 mL of t-butyl methyl etherwas added 1.00 g (4.82 mmol) of n-propyl 3-amino-3-phenylpropionate(racemic mixtures) synthesized in Reference example 2 and the mixturewas maintained to 30° C. To the obtained mixture was added 50 mg oflipase (Amano Lipase PS (trade name); available from AldrichCorporation) originated from Burkholderia cepacia (Pseudomonas cepacia)at the same temperature, and the mixture was reacted while stirring at30° C. After 15 hours, 3 mL of acetone was added to the reaction mixtureand the resulting mixture was filtered to give 359 mg of(S)-3-amino-3-phenylpropionic acid (isolation yield based on n-propyl3-amino-3-phenylpropionate (racemic mixtures)=44.0%) and 37 mg of anenzyme fixing agent as a mixture.

The (S)-3-amino-3-phenylpropionic acid was led to an n-propyl esteraccording to the conventional manner, and when an optical purity thereofwas measured by using high performance liquid chromatography which usesan optically active column, it was 99.9% ee.

When an optical purity of the (R)-n-propyl 3-amino-3-phenylpropionatewas measured by using high performance liquid chromatography which usesan optically active column, it was 99.9% ee.

Incidentally, the E value in the present reaction was larger than 10000.

-   Analytical conditions of high performance liquid chromatography;-   Optically active n-propyl 3-amino-3-phenylpropionate-   Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co.,    Ltd.)-   Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mM

Adjusted to pH 3.5 with phosphoric acid

-   Flow rate: 1.0 mL/min-   Temperatrure: 30° C.-   Wavelength: 220 nm

Also, physical properties of the (S)-3-amino-3-phenylpropionic acid wereas follows.

¹H-NMR (δ (ppm), D₂O+DCl): 3.06 (dd, 1H, J=17.1, 6.8 Hz), 3.17 (dd, 1H,J=17.1, 7.3 Hz), 4.76 (dd, 1H, J=7.3, 6.8 Hz), 3.77 (s, 2H), 7.45 (m,5H)

¹³C-NMR (δ (ppm), D₂O+DCl): 40.5, 54.4, 130.0, 132.3, 132.6, 138.0,176.3

MS (EI) m/z: 165 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 166 (MH⁺)

Elemental analysis; Calcd: C, 65.44%; H, 6.71%; N, 8.48% Found: C,65.18%; H, 6.78%; N, 8.34%.

Physical properties of (R)-n-propyl 3-amino-3-phenylpropionate were asfollows.

¹H-NMR (δ (ppm), CDCl₃): 0.90 (d, 3H, J=7.3 Hz), 1.55-1.65 (tq, 2H,J=7.3, 6.8 Hz), 2.63 (d, 2H, J=6.8 Hz), 4.01 (t, 2H, J=6.8 Hz), 4.39 (d,1H, J=6.8 Hz), 7.20-7.35 (m, 5H)

¹³C-NMR (δ (ppm), CDCl₃): 10.4, 21.9, 44.2, 52.7, 66.1, 126.2, 127.3,128.6, 144.7, 172.0

MS (EI) m/z: 207 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 208 (MH⁺)

Elemental analysis; Calcd: C, 69.54%; H, 8.27%; N, 6.76% Found: C,68.86%; H, 8.22%; N, 6.60%

Example 2 Syntheses of (S)-3-amino-3-phenylpropionic acid and(R)-n-propyl 3-amino-3-phenylpropionate

To a mixed solution comprising 4.75 mL of 50 mmol/L aqueous ammoniumacetate solution with a pH of 8.3 and 0.25 mL of t-butyl methyl etherwas added 1.00 g (4.82 mmol) of n-propyl 3-amino-3-phenylpropionate(racemic mixtures) synthesized in Reference example 2, and the mixturewas maintained to 30° C. To the obtained mixture was added 50 mg oflipase (Amano Lipase PS (trade name); available from AldrichCorporation) originated from Burkholderia cepacia (Pseudomonas cepacia)at the same temperature, and the mixture was reacted while stirring at30° C. After 15 hours, 3 mL of acetone was added to the reaction mixtureand the resulting mixture was filtered to give 359 mg of(S)-3-amino-3-phenylpropionic acid (isolation yield based on n-propyl3-amino-3-phenylpropionate (racemic mixtures)=44.0%) and 38 mg of anenzyme fixing agent as a mixture.

The (S)-3-amino-3-phenylpropionic acid was led to an n-propyl esteraccording to the conventional manner, and when an optical purity thereofwas measured by using high performance liquid chromatography which usesan optically active column, it was 99.8% ee.

When an optical purity of the (R)-n-propyl 3-amino-3-phenylpropionatewas measured by using high performance liquid chromatography which usesan optically active column, it was 79.4% ee.

Incidentally, the E value in the present reaction was 1945.

-   Analytical conditions of high performance liquid chromatography;-   Optically active n-propyl 3-amino-3-phenylpropionate-   Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co.,    Ltd.)-   Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40mM

Adjusted to pH 3.5 with phosphoric acid

-   Flow rate: 1.0 mL/min-   Temperatrure: 30° C.-   Wavelength: 220 nm

Also, physical properties of (S)-3-amino-3-phenylpropionic acid and(R)-n-propyl 3-amino-3-phenylpropionate were the same as those shown inExample 1.

Example 3 Syntheses of (S)-3-amino-3-phenylpropionic acid and(R)-n-propyl 3-amino-3-phenylpropionate

To 4.75 mL of 50 mmol/L aqueous potassium phosphate solution with a pHof 8.2 was added 50 mg of lipase (Amano Lipase PS (trade name);available from Aldrich Corporation) originated from Burkholderia cepacia(Pseudomonas cepacia) and the mixture was stirred at room temperaturefor 30 minutes. The mixture was filtered, and to the resulting filtratewere added 0.25 mL of toluene and 1.00 g (4.82 mmol) of n-propyl3-amino-3-phenylpropionate (racemic mixtures) synthesized in Referenceexample 2, and the mixture was reacted at 30° C. under stirring. After18 hours, 3 mL of acetone was added to the reaction mixture and theresulting mixture was filtered to give 359 mg of(S)-3-amino-3-phenylpropionic acid (isolation yield based on n-propyl3-amino-3-phenylpropionate (racemic mixtures)=44.0%) and 38 mg of anenzyme fixing agent as a mixture.

The (S)-3-amino-3-phenylpropionic acid was led to an n-propyl esteraccording to the conventional manner, and when an optical purity thereofwas measured by using high performance liquid chromatography which usesan optically active column, it was 99.5% ee.

When an optical purity of the (R)-n-propyl 3-amino-3-phenylpropionatewas measured by using high performance liquid chromatography which usesan optically active column, it was 99.9% ee.

Incidentally, the E value in the present reaction was 4038.

-   Analytical conditions of high performance liquid chromatography;-   Optically active n-propyl 3-amino-3-phenylpropionate-   Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co.,    Ltd.)-   Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mM

Adjusted to pH 3.5 with phosphoric acid

-   Flow rate: 1.0 mL/min-   Temperatrure: 30° C.-   Wavelength: 220 nm

Also, physical properties of (S)-3-amino-3-phenylpropionic acid and(R)-n-propyl 3-amino-3-phenylpropionate were the same as those shown inExample 1.

Example 4 Syntheses of (S)-3-amino-3-phenylpropionic acid and(R)-n-propyl 3-amino-3-phenylpropionate

To 1.25 mL of 50 mmol/L aqueous potassium phosphate solution with a pHof 8.2 was added 25 mg of lipase (Amano Lipase PS (trade name);available from Aldrich Corporation) originated from Burkholderia cepacia(Pseudomonas cepacia) and the mixture was stirred at room temperaturefor 30 minutes. The mixture was filtered, 1.25 mL of cyclohexane and 500mg (2.41 mmol) of n-propyl 3-amino-3-phenylpropionate (racemic mixtures)synthesized in Reference example 2 were added to the resulting filtrate,and the mixture was reacted at 30° C. under stirring. After 20 hours,1.5 mL of acetone was added to the reaction mixture and the resultingmixture was stirred at 0° C. for 1 hour. The reaction mixture wasfiltered to give 156 mg of (S)-3-amino-3-phenylpropionic acid (isolationyield based on n-propyl 3-amino-3-phenylpropionate (racemicmixtures)=43.0%). Then, after the filtrate was concentrated underreduced pressure, 2.5 mL of ethyl acetate was added to the residue toextract the organic layer, and the organic layer was dried overanhydrous magnesium sulfate. After filtration, the fitrate wasconcentrated under reduced pressure to give 230 mg of (R)-n-propyl3-amino-3-phenylpropionate (isolation yield based on n-propyl3-amino-3-phenylpropionate (racemic mixtures)=46.0%).

(S)-3-amino-3-phenylpropionic acid was led to an n-propyl esteraccording to the conventional manner, and when an optical purity thereofwas measured by using high performance liquid chromatography which usesan optically active column, it was 99.7% ee.

When an optical purity of the (R)-n-propyl 3-amino-3-phenylpropionatewas measured by using high performance liquid chromatography which usesan optically active column, it was 97.3% ee.

Incidentally, the E value in the present reaction was 3037.

-   Analytical conditions of high performance liquid chromatography;-   Optically active n-propyl 3-amino-3-phenylpropionate-   Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co.,    Ltd.)-   Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mM

Adjusted to pH 3.5 with phosphoric acid

-   Flow rate: 1.0 mL/min-   Temperatrure: 30° C.-   Wavelength: 220 nm

Also, physical properties of the (S)-3-amino-3-phenylpropionic acid and(R)-n-propyl 3-amino-3-phenylpropionate were the same as those shown inExample 1.

Comparative Example 1 Syntheses of (S)-3-amino-3-phenylpropionic acidand (R)-n-propyl 3-amino-3-phenylpropionate

To 1.5 mL of 50 mmol/L aqueous potassium phosphate solution with a pH of8.2 was added 300 mg (1.45 mmol) of n-propyl 3-amino-3-phenylpropionate(racemic mixtures) synthesized in Reference example 2 and the mixturewas maintained to 30° C. To the obtained mixture was added 15 mg oflipase (Amano Lipase PS (trade name); available from AldrichCorporation) originated from Burkholderia cepacia (Pseudomonas cepacia)at the same temperature, and the mixture was reacted while stirring at30° C. After 17 hours, 1.0 mL of acetone was added to the reactionmixture and the resulting mixture was filtered to give 108 mg of(S)-3-amino-3-phenylpropionic acid (isolation yield based on n-propyl3-amino-3-phenylpropionate (racemic mixtures)=45.0%) and 12 mg of anenzyme fixing agent as a mixture.

The (S)-3-amino-3-phenylpropionic acid was led to an n-propyl esteraccording to the conventional manner, and when an optical purity thereofwas measured by using high performance liquid chromatography which usesan optically active column, it was 99.3% ee.

When an optical purity of the (R)-n-propyl 3-amino-3-phenylpropionatewas measured by using high performance liquid chromatography which usesan optically active column, it was 99.9% ee.

Incidentally, the E value in the present reaction was 1687.

-   Analytical conditions of high performance liquid chromatography;-   Optically active n-propyl 3-amino-3-phenylpropionate-   Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co.,    Ltd.)-   Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

-   Flow rate: 1.0 mL/min-   Temperatrure: 30° C.-   Wavelength: 220 nm

Also, physical properties of the (S)-3-amino-3-phenylpropionic acid and(R)-n-propyl 3-amino-3-phenyl-propionate were the same as those shown inExample 1.

Incidentally, determination of the absolute configuration of theoptically active 3-amino-3-phenylpropionic acid was carried out asfollows. A sign of specific rotation ([α]²⁵ _(D)−7.96° (c 1.0, H₂O)) ofthe optically active 3-amino-3-phenylpropionic acid obtained inComparative example 1 and a sigh of specific rotation of(S)-3-amino-3-phenylpropionic acid described in Tetrahedron Asymmetry, 6(7), 1601 (1995) (literature value [α]_(D)−6.42° (c 1.0, H₂O)) arecompared to each other to determine the absolute configuration.

Comparative Example 2 Syntheses of (S)-3-amino-3-phenylpropionic acidand (R)-methyl 3-amino-3-phenylpropionate

To 1.5 mL of 50 mmol/L aqueous potassium phosphate solution with a pH of8.2 was added 300 mg (1.67 mmol) of methyl 3-amino-3-phenylpropionate(racemic mixtures) and the mixture was maintained to 30° C. To theobtained mixture was added 15 mg of lipase (Amano Lipase PS (tradename); available from Aldrich Corporation) originated from Burkholderiacepacia (Pseudomonas cepacia) at the same temperature, and the mixturewas reacted while stirring at 30° C. After 15 hours, 0.5 mL of acetonewas added to the reaction mixture and the resulting mixture was filteredto give 96.8 mg of (S)-3-amino-3-phenylpropionic acid (isolation yieldbased on methyl 3-amino-3-phenylpropionate (racemic mixtures)=35.0%) and10 mg of an enzyme fixing agent as a mixture.

The (S)-3-amino-3-phenylpropionic acid was led to an n-propyl esteraccording to the conventional manner, and when an optical purity thereofwas measured by using high performance liquid chromatography which usesan optically active column, it was 49.9% ee.

When an optical purity of the (R)-methyl 3-amino-3-phenylpropionate wasmeasured by using high performance liquid chromatography which uses anoptically active column, it was 46.8% ee.

Incidentally, the E value in the present reaction was 4.

-   Analytical conditions of high performance liquid chromatography;-   Optically active methyl 3-amino-3-phenylpropionate-   Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co.,    Ltd.)-   Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

-   Flow rate: 0.5 mL/min-   Temperatrure: 30° C.-   Wavelength: 220 nm

Also, physical properties of the (S)-3-amino-3-phenylpropionic acid werethe same as those shown in Example 1.

Comparative example 3 Syntheses of (S)-3-amino-3-phenylpropionic acidand (R)-ethyl 3-amino-3-phenylpropionate

To 1.5 mL of 50 mmol/L aqueous potassium phosphate solution with a pH of8.2 was added 300 mg (1.55 mmol) of ethyl 3-amino-3-phenylpropionate(racemic mixtures) and the mixture was maintained to 30° C. To theobtained mixture was added 13 mg of lipase (Amano Lipase PS (tradename); available from Aldrich Corporation) originated from Burkholderiacepacia (Pseudomonas cepacia) at the same temperature, and the mixturewas reacted while stirring at 30° C. After 13 hours, 0.5 mL of acetonewas added to the reaction mixture and the resulting mixture was filteredto give 103 mg of (S)-3-amino-3-phenylpropionic acid (isolation yieldbased on ethyl 3-amino-3-phenylpropionate (racemic mixtures)=40.0%) and10 mg of an enzyme fixing agent as a mixture.

The (S)-3-amino-3-phenylpropionic acid was led to an n-propyl esteraccording to the conventional manner, and when an optical purity thereofwas measured by using high performance liquid chromatography which usesan optically active column, it was 98.8% ee.

When an optical purity of the (R)-ethyl 3-amino-3-phenylpropionate wasmeasured by using high performance liquid chromatography which uses anoptically active column, it was 95.3% ee.

Incidentally, the E value in the present reaction was 628.

-   Analytical conditions of high performance liquid chromatography;-   Optically active ethyl 3-amino-3-phenylpropionate-   Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co.,    Ltd.)-   Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

-   Flow rate: 0.5 mL/min-   Temperatrure: 30° C.-   Wavelength: 220 nm

Also, physical properties of the (S)-3-amino-3-phenylpropionic acid werethe same as those shown in Example 1.

Physical properties of the (R)-ethyl 3-amino-3-phenylpropionate were asfollows.

¹H-NMR (δ (ppm), CDCl₃): 1.19 (t, 3H, J=7.3 Hz), 3.15 (dd, 1H, J=7.3,16.6 Hz), 3.25 (dd, 1H, J=7.3, 16.6 Hz), 4.15 (q, 2H, J=7.3 Hz), 4.85(dd, 1H, J=7.3, 7.3 Hz), 7.50-7.55 (m, 5H)

¹³C-NMR (δ (ppm), CDCl₃): 16.0, 40.9, 54.3, 65.2, 129.9, 132.2, 132.5,137.8, 174.3

Comparative Example 4 Syntheses of (S)-3-amino-3-phenylpropionic acidand (R)-isopropyl 3-amino-3-phenylpropionate

To 1.5 mL of 50 mmol/L aqueous potassium phosphate solution with a pH of8.2 was added 300 mg (1.45 mmol) of isopropyl 3-amino-3-phenylpropionate(racemic mixtures) and the mixture was maintained to 30° C. To theobtained mixture was added 15 mg of lipase (Amano Lipase PS (tradename); available from Aldrich Corporation) originated from Burkholderiacepacia (Pseudomonas cepacia) at the same temperature, and the mixturewas reacted while stirring at 30° C. for 3 hours. However, the reactiondis not substantially proceed, and the objective product could not beobtained.

-   Analytical conditions of high performance liquid chromatography;-   Isopropyl 3-amino-3-phenylpropionate (racemic mixtures) and    3-amino-3-phenylpropionic acid (racemic mixtures)-   Column: Cadenza CD-C18 (4.6 cmΦ×50 mm, available from DAICEL    CHEMICAL INDUSTRIES, LTD.)-   Solvent: acetonitrile/water (=2/3 (volume ratio))

Potassium dihydrogen phosphate: 10 mmol/L

pH 6.0

-   Wavelength: 254 nm-   Flow rate: 0.6 mL/min-   Temperatrure: 40° C.

Reference example 3 Syntheses of t-butyl 3-amino-3-phenyl-propionate(racemic mixtures)

To 25.0 mL (0.27 mol) of n-butyl alcohol were added 5.00 g (30.3 mmol)of 3-amino-3-phenylpropionic acid (racemic mixtures) synthesized inReference example 1 and 6.00 g (61.2 mmol) of conc. sulfuric acid, andthe mixture was reacted while stirring at 70 to 80° C. for 4 hours.After completion of the reaction, 10 mL of water and 6 mol/L aqueoussodium hydroxide solution were added to the obtained reaction mixture toadjust a pH of the reaction mixture to 7 to 8. Then, 1 g of sodiumchloride was added to the mixture, the liquids were separated, and then,the organic layer was dried over anhydrous magnesium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure to give6.90 g of t-butyl 3-amino-3-phenylpropionate (racemic mixtures)(isolation yield based on 3-amino-3-phenylpropionic acid (racemicmixtures): 88.1%) as colorless liquid.

Incidentally, physical properties of the n-butyl3-amino-3-phenylpropionate (racemic mixtures) were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.90 (t, 3H, J=7.3 Hz), 1.32 (tq, 2H, J=7.6,7.3 Hz), 1.56 (dt, 2H, J=7.6, 6.8 Hz), 1.91 (s, 2H)2.64 (d, 2H, J=6.8Hz), 4.06 (t, 2H, J=6.8 Hz), 4.39 (t, 1H, J=6.8 Hz), 7.20-7.35 (m, 5H)

¹³C-NMR (δ (ppm), CDCl₃) : 13.7, 19.1, 30.644.1, 52.7, 64.4, 126.2,127.4, 128.6, 144.6, 172.0

-   MS (EI) m/z: 221 (M⁺)-   MS (CI, i-C₄H₁₀) m/z: 222 (MH⁺)

Example 5 Syntheses of (S)-3-amino-3-phenylpropionic acid and(R)-n-butyl 3-amino-3-phenylpropionate

To a mixture comprising 500 mg (2.26 mmol) of n-butyl3-amino-3-phenylpropionate (racemic mixtures) synthesized in Referenceexample 3 and 1.25 mL of cyclohexane was added 1.25 mL of 50 mmol/Laqueous potassium phosphate solution with a pH of 8.2 and the mixturewas maintained to 30° C. To the obtained mixture was added 25 mg oflipase (Amano Lipase PS (trade name); available from AldrichCorporation) originated from Burkholderia cepacia (Pseudomonas cepacia)at the same temperature, and the mixture was reacted while stirring at30° C. After 59 hours, a reaction conversion reached 45.4%.

The n-Butyl (R)-3-amino-3-phenylpropionate was led to (R)-n-butyl3-(2-furoylamino)-3-phenylpropionate, and when an optical purity thereofwas measured by using high performance liquid chromatography which usesan optically active column, it was 82.2% ee.

Incidentally, the E value in the present reaction was 513.

-   Optically active n-butyl 3-(2-furoylamino)-3-phenylpropionate-   Column: Chiralcel OJ-H (0.46 cmΦ×25 cm, available from DAICEL    CHEMICAL INDUSTRIES, LTD.)-   Solvent: hexane/isopropyl alcohol (=1/9 (volume ratio))-   Flow rate: 0.5 mL/min-   Temperatrure: 30° C.-   Wavelength: 220 nm

Also, physical properties of the (S)-3-amino-3-phenylpropionic acid werethe same as those shown in Example 1.

Physical properties of the (R)-n-butyl 3-amino-3-phenylpropionate wereas follows.

¹H-NMR (δ (ppm), CDCl₃): 0.90 (t, 3H, J=7.3 Hz), 1.32 (tq, 2H, J=7.6,7.3 Hz), 1.56 (dt, 2H, J=7.6, 6.8 Hz), 1.91 (s, 2H)2.64 (d, 2H, J=6.8Hz), 4.06 (t, 2H, J=6.8 Hz), 4.39 (t, 1H, J=6.8 Hz), 7.20-7.35 (m, 5H)

¹³C-NMR (δ (ppm), CDCl₃) : 13.7, 19.1, 30.644.1, 52.7, 64.4, 126.2,127.4, 128.6, 144.6, 172.0

MS (EI) m/z: 221 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 222 (MH⁺)

Example 6 Synthesis of 3-amino-3-(4-tolyl)propionic acid (racemicmixtures)

To 250 mL of ethanol were added 50.0 g (0.42 mol) of 4-tolylaldehyde,47.6 g (0.46 mol) of malonic acid and 64.2 g (0.83 mol) of ammoniumacetate, and the mixture was reacted while stirring under reflux (80 to90° C.) for 7.5 hours. The obtained reaction mixture was stirred at 0 to5° C. for 30 minutes and then filtered to give 51.4 g of3-amino-3-(4-tolyl)propionic acid (racemic mixtures) (isolation yieldbased on 4-tolylaldehyde: 68.9%) as white powder.

Incidentally, physical properties of the 3-amino-3-(4-tolyl)propionicacid (racemic mixtures) were as follows.

¹H-NMR (δ (ppm), D₂O+DCl): 2.30 (s, 3H), 3.04 (dd, 1H, J=17.1, 6.8 Hz),3.20 (dd, 1H, J=17.1, 7.3 Hz), 4.74 (dd, 1H, J=7.3, 6.8 Hz), 7.29 (d,2H, 8.3 Hz), 7.36 (d, 2H, 8.3 Hz)

¹³C-NMR (δ (ppm), D₂O+DCl): 23.4, 40.7, 54.4, 130.0, 133.0, 135.0,143.1, 176.3

MS (EI) m/z: 179 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 180 (MH⁺)

Elemental analysis; Calcd: C, 67.02%; H, 7.31%; N, 7.82% Found: C,67.05%; H, 7.40%; N, 7.66%

Example 7 Syntheses of n-propyl 3-amino-3-(4-tolyl)propionate (racemicmixtures)

To 50.0 mL (1.03 mol) of n-propyl alcohol were added 10.0 g (55.8 mmol)of 3-amino-3-(4-tolyl)propionic acid (racemic mixtures) synthesized inExample 6 and 8.20 g (83.6 mmol) of conc. sulfuric acid, and the mixturewas reacted while stirring at 60° C. for 4 hours. After completion ofthe reaction, the obtained reaction mixture was concentrated underreduced pressure, and then 28% aqueous ammonia was added thereto toadjust a pH of the reaction mixture to 8.5. Then, 50 mL of ethyl acetateand 20 mL of water were added to the mixture to carry out extraction,and the organic layer was dried over anhydrous magnesium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure to give10.9 g of n-propyl 3-amino-3-(4-tolyl)propionate (racemic mixtures)(isolation yield based on 3-amino-3-(4-tolyl)propionic acid (racemicmixtures): 88.0%) as colorless liquid.

Incidentally, physical properties of the n-propyl3-amino-3-(4-tolyl)propionate (racemic mixtures) were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.90 (t, 3H, J=7.3 Hz), 1.62 (tq, 2H, J=7.3,6.8 Hz), 2.30 (s, 3H), 2.62 (d, 2H, J=6.8 Hz), 4.02 (t, 2H, J=6.8 Hz),4.36 (d, 1H, J=6.8 Hz), 7.11 (d, 2H, 8.3 Hz), 7.23 (d, 2H, 8.3 Hz)

¹³C-NMR (δ (ppm), CDCl₃): 10.4, 21.0, 22.0, 44.2, 52.4, 66.0, 126.1,129.2, 136.8, 141.9, 172.1 MS (EI) m/z: 221 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 222 (MH⁺)

Comparative Example 5 Syntheses of (S or R)-3-amino-3-(4-tolyl)propionicacid and (R or S)-n-propyl 3-amino-3-(4-tolyl)propionate

To 2.5 mL of 50 mmol/L aqueous potassium phosphate solution with a pH of8.2 was added 500 mg (2.26 mmol) of 3-amino-3-(4-tolyl)propionic acidn-propyl ester (racemic mixtures) synthesized in Example 7 and themixture was maintained to 30° C. To the obtained mixture was added 25 mgof lipase (Amano Lipase PS (trade name); available from AldrichCorporation) originated from Burkholderia cepacia (Pseudomonas cepacia)at the same temperature, and the mixture was reacted while stirring at30° C. After 16 hours, 1 mL of acetone was added to the reaction mixtureand the resulting mixture was filtered to give 364 mg of (S orR)-3-amino-3-(4-tolyl)propionic acid (isolation yield based on n-propyl3-amino-3-(4-tolyl)propionate (racemic mixtures)=45.0%) and 20 mg of anenzyme fixing agent as a mixture.

The (S or R)-3-amino-3-(4-tolyl)propionic acid was led to an n-propylester according to the conventional manner, and when an optical puritythereof was measured by using high performance liquid chromatographywhich uses an optically active column, it was 98.7% ee.

When an optical purity of the (R or S)-n-propyl3-amino-3-(4-tolyl)propionate was measured by using high performanceliquid chromatography which uses an optically active column, it was98.6% ee.

Incidentally, the E value in the present reaction was 772.

Analytical conditions of high performance liquid chromatography;

Optically active n-propyl 3-amino-3-(4-tolyl)propionate

Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co., Ltd.)

Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 1.0 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S or R)-3-amino-3-(4-tolyl)propionicacid were as follows.

¹H-NMR (δ (ppm), D₂O+DCl): 2.30 (s, 3H) , 3.04 (dd, 1H, J=17.1, 6.8 Hz),3.20 (dd, 1H, J=17.1, 7.3 Hz), 4.74 (dd, 1H, J=7.3, 6.8 Hz), 7.29 (d,2H, 8.3 Hz), 7.36 (d, 2H, 8.3 Hz)

¹³C-NMR (δ (ppm), D₂O+DCl): 23.4, 40.7, 54.4, 130.0, 133.0, 135.0,143.1, 176.3

MS (EI) m/z: 179 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 180 (MH⁺)

Elemental analysis; Calcd: C, 67.02%; H, 7.31%; N, 7.82%

Found: C, 67.05%; H, 7.40%; N, 7.66%

Specific rotation: [α]²⁵ _(D)+2.930 (c 1.0, 2N HCl)

Physical properties of the (R or S)-n-propyl3-amino-3-(4-tolyl)propionate were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.90 (t, 3H, J=7.3 Hz), 1.62 (tq, 2H, J=7.3,6.8 Hz), 2.30 (s, 3H), 2.62 (d, 2H, J=6.8 Hz), 4.02 (t, 2H, J=6.8 Hz),4.36 (d, 1H, J=6.8 Hz), 7.11 (d, 2H, 8.3 Hz), 7.23 (d, 2H, 8.3 Hz)

¹³C-NMR (δ (ppm), CDCl₃): 10.4, 21.0, 22.0, 44.2, 52.4, 66.0, 126.1,129.2, 136.8, 141.9, 172.1

MS (EI) m/z: 221 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 222 (MH⁺)

Example 8 Syntheses of (S or R)-3-amino-3-(4-tolyl)propionic acid and (Ror S)-n-propyl 3-amino-3-(4-tolyl)propionate

To 4.75 mL of 10 mmol/L aqueous potassium phosphate solution with a pHof 8.2 was added 50 mg of lipase (Amano Lipase PS (trade name);available from Aldrich Corporation) originated from Burkholderia cepacia(Pseudomonas cepacia) and the mixture was stirred at room temperaturefor 30 minutes. The mixture was filtered, and to the obtained filtratewere added 0.25 mL of t-butyl methyl ether and 1.00 g (4.52 mmol) of3-amino-3-(4-tolyl)propionic acid n-propyl ester (racemic mixtures)synthesized in Example 7, and the mixture was reacted while stirring at30° C. After 16 hours, 3 mL of acetone was added to the reaction mixtureand the resulting mixture was filtered to give 348 mg of (S orR)-3-amino-3-(4-tolyl)propionic acid (yield based on n-propyl3-amino-3-(4-tolyl)propionate (racemic mixtures)=43.0%). Then, after thefiltrate was concentrated under reduced pressure, 10 mL of ethylacetate, 5 mL of water and 6 mol/L aqueous sodium hydroxide solutionwere added to the concentrate to adjust a pH to 8.0. The organic layerwas collected by separation and dried over anhydrous magnesium sulfate.After filtration, the filtrate was concentrated under reduced pressureto give 450 mg of (R or S)-n-propyl 3-amino-3-phenylpropionate(isolation yield based on n-propyl 3-amino-3-phenylpropionate (racemicmixtures)=45.0%).

The (S or R)-3-amino-3-(4-tolyl)propionic acid was led to an n-propylester according to the conventional manner, and when an optical puritythereof was measured by using high performance liquid chromatographywhich uses an optically active column, it was 97.1% ee.

When an optical purity of the (R or S)-n-propyl3-amino-3-(4-tolyl)propionate was measured by using high performanceliquid chromatography which uses an optically active column, it was99.9% ee.

Incidentally, the E value in the present reaction was 663.

Analytical conditions of high performance liquid chromatography;

Optically active n-propyl 3-amino-3-(4-tolyl)propionate

Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co., Ltd.)

Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 1.0 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S or R)-3-amino-3-(4-tolyl)propionicacid and (R or S)-n-propyl 3-amino-3-(4-tolyl)propionate were the sameas those shown in Comparative example 5.

Example 9 Syntheses of (S or R)-3-amino-3-(4-tolyl)propionic acid and (Ror S)-n-propyl 3-amino-3-(4-tolyl)propionate

To 10 mL of 10 mmol/L aqueous potassium phosphate solution with a pH of8.2 was added 200 mg of lipase (Amano Lipase PS (trade name); availablefrom Aldrich Corporation) originated from Burkholderia cepacia(Pseudomonas cepacia) and the mixture was stirred at room temperaturefor 30 minutes. The mixture was filtered, to the obtained filtrate wereadded 10 mL of t-butyl methyl ether and 4.00 g (18.1 mmol) of n-propyl3-amino-3-(4-tolyl)propionate (racemic mixtures) synthesized in Example7, and the mixture was reacted while stirring at 30° C. After 16 hours,1 mL of ethanol was added to the reaction mixture and the resultingmixture was filtered to give 1.49 g of (S orR)-3-amino-3-(4-tolyl)propionic acid (yield based on n-propyl3-amino-3-(4-tolyl)propionate (racemic mixtures)=46.0%). Then, after thefiltrate was concentrated under reduced pressure, 10 mL of ethylacetate, 5 mL of water and 6 mol/L aqueous sodium hydroxide solutionwere added to the concentrate to adjust a pH to 8.5. The organic layerwas collected by separation and dried over anhydrous magnesium sulfate.After filtration, the filtrate was concentrated to give 2 g of (R orS)-n-propyl 3-amino-3-phenylpropionate (isolation yield based onn-propyl 3-amino-3-phenylpropionate (racemic mixtures)=45.0%).

The (S or R)-3-amino-3-(4-tolyl)propionic acid was led to an n-propylester according to the conventional manner, and when an optical puritythereof was measured by using high performance liquid chromatographywhich uses an optically active column, it was 99.7% ee.

When an optical purity of the (R or S)-n-propyl3-amino-3-(4-tolyl)propionate was measured by using high performanceliquid chromatography which uses an optically active column, it was96.8% ee.

Incidentally, the E value in the present reaction was 3321.

Analytical conditions of high performance liquid chromatography;

Optically active 3-amino-3-(4-tolyl)propionic acid n-propyl ester

Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co., Ltd.)

Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 1.0 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S or R)-3-amino-3-(4-tolyl)propionicacid and (R or S)-n-propyl 3-amino-3-(4-tolyl)propionate were the sameas those shown in Comparative example 5.

Comparative Example 6 Syntheses of (S)-3-amino-3-(4-tolyl)propionic acidand (R)-ethyl 3-amino-3-(4-tolyl)-propionate

To 2.5 mL of 50 mmol/L aqueous potassium phosphate solution with a pH of8.2 was added 500 mg (2.41 mol) of ethyl 3-amino-3-(4-tolyl)propionate(racemic mixtures) and the mixture was maintained to 30° C., 25 mg oflipase (Amano Lipase PS (trade name); available from AldrichCorporation) originated from Burkholderia cepacia (Pseudomonas cepacia)was added to the mixture at the same temperature, and the mixture wasreacted while stirring at 30° C. After 16 hours, 1.0 mL of acetone wasadded to the reaction mixture and the resulting mixture was filtered togive 173 mg of (S)-3-amino-3-(4-tolyl)propionic acid (isolation yieldbased on ethyl 3-amino-3-(4-tolyl)propionate (racemic mixtures)=40.0%)and 20 mg of an enzyme fixing agent as a mixture.

The (S)-3-amino-3-(4-tolyl)propionic acid was led to an ethyl esteraccording to the conventional manner, and when an optical purity thereofwas measured by using high performance liquid chromatography which usesan optically active column, it was 88.4% ee.

When an optical purity of the (R)-ethyl 3-amino-3-(4-tolyl)propionatewas measured by using high performance liquid chromatography which usesan optically active column, it was 47.2% ee.

Incidentally, the E value in the present reaction was 26.

Analytical conditions of high performance liquid chromatography;

Optically active ethyl 3-amino-3-(4-tolyl)propionate Column: ChiralCD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co., Ltd.)

Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S)-3-amino-3-(4-tolyl)propionic acidwere the same as those shown in Comparative example 5.

Physical properties of the (R)-ethyl 3-amino-3-(4-tolyl)propionate wereas follows.

H-NMR (δ (ppm), CDCl₃): 1.20 (t, 3H, J=7.3 Hz), 2.36 (s, 3H), 3.11 (dd,1H, J=7.8, 16.6 Hz), 3.26 (dd, 1H, J=6.3, 16.6 Hz), 4.11-4.18 (m, 2H),4.82 (dd, 1H, J=6.3, 7.8 Hz), 7.35 (d, 2H, J=7.8 Hz), 7.42 (d, 2H, J=8.3Hz)

¹³C-NMR (δ (ppm), CDCl₃): 16.1, 23.1, 41.1, 54.2, 65.2, 129.9, 132.8,134.9, 142.9, 174.3

Example 10 Synthesis of n-butyl 3-amino-3-(4-tolyl)propionate (racemicmixtures)

To 60.0 mL (652 mmol) of n-butyl alcohol were added 6.00 g (25.0 mmol)of 3-amino-3-(4-tolyl)propionic acid (racemic mixtures) synthesized inExample 6 and 4.90 g (50.2 mmol) of conc. sulfuric acid, and the mixturewas reacted while stirring at 55 to 60° C. for 3 hours. After completionof the reaction, 12 mL of water was added to the reaction mixture, a pHof the mixture was adjusted to 7.0 with 6 mol/L sodium hydroxide and themixture was concentrated under reduced pressure. To the obtainedconcentrated residue was added 30 mL of cyclohexane, and a pH of themixture was adjusted to 9.5 with 6 mol/L aqueous sodium hydroxidesolution. The obtained mixture was allowed to stand, liquids wereseparated and the extracted organic phase was dried over anhydrousmagnesium sulfate. After filtration, the filtrate was concentrated underreduced pressure to give 6.70 g of t-butyl3-amino-3-(4-tolyl)-propionate (racemic mixtures) (isolation yield basedon 3-amino-3-(4-tolyl)propionic acid (racemic mixtures): 85%) ascolorless liquid.

Incidentally, physical properties of the n-butyl3-amino-3-(4-tolyl)propionate (racemic mixtures) were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.91 (t, 3H, J=7.3 Hz), 1.22-1.42 (m, 2H),1.51-1.62 (m, 2H), 2.33 (s, 5H), 2.68 (d, 6.8 Hz), 4.07 (t, 1H, 6.8 Hz),4.40 (t, 2H, 6.8 Hz), 7.13-7.27 (m, 4H)

¹³C-NMR (δ (ppm), CDCl₃): 13.69, 19.12, 21.05, 30.64, 43.82, 52.36,64.45, 126.20, 129.31, 137.13, 144.54, 172.01

MS (EI) m/z: 235 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 236 (MH⁺)

Example 11 Syntheses of (S or R)-3-amino-3-(4-tolyl)propionic acid and(R or S)-n-butyl 3-amino-3-(4-tolyl)-propionate

To a mixture comprising 500 mg (2.22 mmol) of3-amino-3-(4-tolyl)propionic acid n-butyl ester (racemic mixtures)synthesized in Example 10 and-1.25 mL of cyclohexane was added 1.25 mLof 50 mmol/L aqueous potassium phosphate solution with a pH of 8.2 andthe mixture was maintained to 30° C. To the obtained mixture was added25 mg of lipase (Amano Lipase PS (trade name); available from AldrichCorporation) originated from Burkholderia cepacia (Pseudomonas cepacia)at the same temperature, and the mixture was reacted while stirring at30° C. After 40 hours, a reaction conversion reached 50.6%.

When an optical purity of the (S or R)-3-amino-3-(4-tolyl)propionic acidwas measured by using high performance liquid chromatography which usesan optically active column, it was 97.3% ee.

The (R or S)-n-butyl 3-amino-3-(4-tolyl)propionate was led to (R orS)-n-butyl 3-(2-furoylamino)-3-(4-tolyl)-propionate, and when an opticalpurity thereof was measured by using high performance liquidchromatography which uses an optically active column, it was 99.4% ee.

Incidentally, the E value in the present reaction was 421.

Analytical conditions of high performance liquid chromatography;

Optically active 3-amino-3-(4-tolyl)propionic acid

Column: Chiral CD-Ph (0.46 cmΦ×25 cm×2 columns connected, available fromShiseido Co., Ltd.)

Solvent: acetonitrile/water (=5/95 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Optically active n-butyl 3-(2-furoylamino)-3-(4-tolyl)-propionate

Column: Chiralcel OJ-H (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=1/9 (volume ratio))

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S or R)-3-amino-3-(4-tolyl)propionicacid were the same as those shown in Comparative example 5.

Physical properties of the (R or S)-n-butyl3-amino-3-(4-tolyl)propionate (racemic mixtures) were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.91 (t, 3H, J=7.3 Hz), 1.22-1.42 (m, 2H),1.51-1.62 (m, 2H), 2.33 (s, 5H), 2.68 (d, 6.8 Hz), 4.07 (t, 1H, 6.8 Hz),4.40 (t, 2H, 6.8 Hz), 7.13-7.27 (m, 4H)

¹³C-NMR (δ (ppm), CDCl₃): 13.69, 19.12, 21.05, 30.64, 43.82, 52.36,64.45, 126.20, 129.31, 137.13, 144.54, 172.01

MS (EI) m/z: 235 (M⁺)

MS (CI, i-C₃H₁₀) m/z: 236 (MH⁺)

Example 12 Synthesis of 3-amino-3-(4-chlorophenyl)propionic acid(racemic mixtures)

To 25 mL of ethanol were added 5.00 g (35.6 mmol) of4-chlorobenzaldehyde, 3.70 g (35.6 mmol) of malonic acid and 4.10 g(53.2 mmol) of ammonium acetate, and the mixture was reacted whilestirring under reflux (75 to 80° C.) for 8 hours. After completion ofthe reaction, the obtained reaction mixture was stirred at roomtemperature for 1 hour and then filtered to give 5.9 g of3-amino-3-(4-chlorophenyl)propionic acid (racemic mixtures) (isolationyield based on 4-chlorobenzaldehyde: 82.3%) as white powder.

Incidentally, physical properties of the3-amino-3-(4-chlorophenyl)propionic acid (racemic mixtures) were asfollows.

¹H-NMR (δ (ppm), D₂O): 2.93 (dd, 1H, J=17.1, 6.8 Hz), 3.04 (dd, 1H,J=17.1, 7.8 Hz), 4.63 (dd, 1H, J=7.8, 6.8 Hz), 7.22 (s, 1H), 7.24 (s,1H), 7.47 (s, 1H), 7.49 (s, 1H)

¹³C-NMR (δ (ppm), D₂O): 40.4, 53.9, 126.0, 131.9, 135.3, 137.1, 175.9

MS (EI) m/z: 199 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 200 (MH⁺)

Example 13 Synthesis of n-propyl 3-amino-3-(4-chlorophenyl)propionate(racemic mixtures)

To 20.0 mL (258 mmol) of n-propyl alcohol were added 5.00 g (25.0 mmol)of 3-amino-3-(4-chlorophenyl)propionic acid (racemic mixtures)synthesized in Example 12 and 3.90 g (39.8 mmol) of conc. sulfuric acid,and the mixture was reacted while stirring at 55 to 60° C. for 2.5hours. At the same temperature, the solvent was removed by distillationfrom the reaction system with a predetermined amount, and the sameamount of n-propyl alcohol to that of the removed solvent was added tothe mixture and the reaction was continued. After completion of thereaction, 10 mL of water was added to the reaction mixture, a pH of themixture was adjusted to 7.5 with 6 mol/L sodium hydroxide and themixture was concentrated under reduced pressure. To the obtainedconcentrated residue was added 25 mL of t-butyl methyl ether, a pH ofthe mixture was adjusted to 10.1 by using 6 mol/L aqueous sodiumhydroxide solution. The obtained mixture was allowed to stand, liquidswere separated and the extracted organic phase was dried over anhydrousmagnesium sulfate. After filtration, the filtrate was concentrated underreduced pressure to give 4.89 g of n-propyl3-amino-3-(4-chlorophenyl)propionate (racemic mixtures) (isolation yieldbased on 3-amino-3-(4-chlorophenyl)propionic acid (racemic mixtures):80.8%) as colorless liquid.

Incidentally, physical properties of the n-propyl3-amino-3-(4-chlorophenyl)propionate (racemic mixtures) were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.91 (t, 3H, J=7.8 Hz), 1.62 (qt, 2H, 7.8, 6.8Hz), 1.72 (br, 2H), 2.63 (d, 2H, J=6.8 Hz), 4.04 (t, 2H, 6.8 Hz), 4.41(t, 2H, 6.8 Hz), 7.31 (s, 4H)

¹³C-NMR (δ (ppm), CDCl₃): 10.4, 21.9, 44.1, 52.1, 66.3, 127.7, 128.7,133.1, 143.2, 171.8

MS (EI) m/z: 241 (M⁺)

MS (CI, i-C₃H₁₀) m/z: 242 (MH⁺)

Example 14 Syntheses of (S or R)-3-amino-3-(4-chlorophenyl)propionicacid and (R or S)-n-propyl 3-amino-3-(4-chlorophenyl)propionate)

To 0.75 mL of 10 mmol/L aqueous potassium phosphate solution with a pHof 8.2 was added 15 mg of lipase (Amano Lipase PS (trade name);available from Aldrich Corporation) originated from Burkholderia cepacia(Pseudomonas cepacia) at the same temperature and the mixture wasstirred at room temperature for 30 minutes. The mixture was filtered, tothe obtained filtrate were added 0.75 mL of t-butyl methyl ether and 300mg (1.2 mmol) of n-propyl 3-amino-3-(4-chlorophenyl)propionate (racemicmixtures) synthesized in Example 13, and the mixture was reacted whilestirring at 30° C.

After 5 hours, 1.0 mL of acetone was added to the reaction mixture andthe resulting mixture was filtered to give 112 mg of (S orR)-3-amino-3-(4-chlorophenyl)propionic acid (yield based on n-propyl3-amino-3-(4-chlorophenyl)propionate (racemic mixtures)=45.0%). Then,the filtrate was separated, the organic phase was extracted and driedover anhydrous magnesium sulfate, and after filtration, the filtrate wasconcentrated to give 135 mg of (R or S)-n-propyl3-amino-3-(4-chlorophenyl)propionate (isolation yield based on n-propyl3-amino-3-(4-chloro-phenyl)propionate (racemic mixtures)=45.0%).

The (S or R)-3-amino-3-(4-chlorophenyl)propionic acid was led to ann-propyl ester according to the conventional manner, and when an opticalpurity thereof was measured by using high performance liquidchromatography which uses an optically active column, it was 99.8% ee.

When an optical purity of the (R or S)-n-propyl3-amino-3-(4-chlorophenyl)propionate was measured by using highperformance liquid chromatography which uses an optically active column,it was 94.6% ee.

Incidentally, the E value in the present reaction was 4664.

Analytical conditions of high performance liquid chromatography;

Optically active n-propyl 3-amino-3-(4-chlorophenyl)-propionate,

Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co., Ltd.)

Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 1.0 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(4-chlorophenyl)propionic acid were as follows.

¹H-NMR (8 (ppm), D₂O): 2.93 (dd, 1H, J=17.1, 6.8 Hz), 3.04 (dd, 1H,J=17.1, 7.8 Hz), 4.63 (dd, 1H, J=7.8, 6.8 Hz), 7.22 (s, 1H), 7.24 (s,1H), 7.47 (s, 1H), 7.49 (s, 1H)

¹³C-NMR (δ (ppm), D₂O): 40.4, 53.9, 126.0, 131.9, 135.3, 137.1, 175.9

MS (EI) m/z: 199 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 200 (MH⁺)

Physical properties of the (R or S)-n-propyl3-amino-3-(4-chlorophenyl)propionate were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.91 (t, 3H, J=7.8 Hz), 1.62 (qt, 2H, 7.8, 6.8Hz), 1.72 (br, 2H), 2.63 (d, 2H, J=6.8 Hz), 4.04 (t, 2H, 6.8 Hz), 4.41(t, 2H, 6.8 Hz), 7.31 (s, 4H)

¹³C-NMR (δ (ppm), CDCl₃): 10.4, 21.9, 44.1, 52.1, 66.3, 127.7, 128.7,133.1, 143.2, 171.8

MS (EI) m/z: 241 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 242 (MH⁺)

Comparative Example 7 Syntheses of (S orR)-3-amino-3-(4-chlorophenyl)propionic acid and (R or S)-ethyl3-amino-3-(4-chlorophenyl)propionate

To a mixed solution comprising 0.75 mL of 50 mmol/L aqueous potassiumphosphate solution with a pH of 8.2 and 0.75 mL of t-butyl methyl etherwas added 300 mg (1.3 mmol) of ethyl3-amino-3-(4-chlorophenyl)propionate (racemic mixtures), and the mixturewas maintained to 30° C., 15 mg of lipase (Amano Lipase PS (trade name);available from Aldrich Corporation) originated from Burkholderia cepacia(Pseudomonas cepacia) was added to the mixture at the same temperature,and the mixture was reacted while stirring at 30° C. After 5 hours, 1.0mL of acetone was added to the reaction mixture and the resultingmixture was filtered to give 113 mg of (S orR)-3-amino-3-(4-chlorophenyl)propionic acid (isolation yield based onethyl 3-amino-3-(4-chlorophenyl)propionate (racemic mixtures)=43.0%) and12 mg of an enzyme fixing agent as a mixture. Then, the filtrate wasseparated, and the organic phase was extracted and dried over anhydrousmagnesium sulfate, and after filtration, the filtrate was concentratedto give 135 mg of (R or S)-ethyl 3-amino-3-(4-chlorophenyl)propionate(isolation yield based on ethyl 3-amino-3-(4-chlorophenyl)propionate(racemic mixtures)=45.0%).

The (S or R)-3-amino-3-(4-chlorophenyl)propionic acid was led to ann-propyl ester according to the conventional manner, and when an opticalpurity thereof was measured by using high performance liquidchromatography which uses an optically active column, it was 99.3% ee.

When an optical purity of the (R or S)-ethyl3-amino-3-(4-chlorophenyl)propionate was measured by using highperformance liquid chromatography which uses an optically active column,it was 99.0% ee.

Incidentally, the E value in the present reaction was 1757.

Analytical conditions of high performance liquid chromatography;

Optically active ethyl 3-amino-3-(4-chlorophenyl)propionate,

Optically active n-propyl 3-amino-3-(4-chlorophenyl)propionate

Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co., Ltd.)

Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(4-chlorophenyl)propionic acid were the same as those shownin Example 14.

Physical properties of the (R or S)-ethyl3-amino-3-(4-chlorophenyl)propionate were as follows.

¹H-NMR (δ (ppm), CDCl₃): 1.23 (t, 3H, J=7.1 Hz), 1.71 (br, 2H), 2.62 (d,2H, J=6.8 Hz), 4.14 (q, 2H7.1 Hz), 4.40 (t, 1H, d=6.8 Hz), 7.30 (s, 4H)

¹³C-NMR (δ (ppm), CDCl₃): 14.1, 44.1, 52.0, 60.6, 127.6, 128.7, 133.0,143.1, 171.7

MS (EI) m/z: 227 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 228 (MH⁺)

Example 15 Synthesis of 3-amino-3-(4-bromophenyl)propionic acid (racemicmixtures)

To 30 mL of ethanol were added 5.00 g (27.0 mmol) of4-bromobenzaldehyde, 2.80 g (27.0 mmol) of malonic acid and 3.10 g (40.2mmol) of ammonium acetate, and the mixture was reacted while stirringunder reflux (75 to 80° C.) for 10 hours. After completion of thereaction, the obtained reaction mixture was stirred at room temperaturefor 1 hour and then filtered to give 4.8 g of3-amino-3-(4-bromophenyl)propionic acid (racemic mixtures) (isolationyield based on 4-bromobenzaldehyde: 72.2%) as white powder.

Incidentally, physical properties of the3-amino-3-(4-bromophenyl)propionic acid (racemic mixtures) were asfollows.

¹H-NMR (δ (ppm), D₂O): 2.93 (dd, 1H, J=17.1, 6.8 Hz), 3.04 (dd, 1H,J=17.1, 7.8 Hz), 4.63 (dd, 1H, J=7.8, 6.8 Hz), 7.22 (s, 1H), 7.24 (s,1H), 7.47 (s, 1H), 7.49 (s, 1H)

¹³C-NMR (δ (ppm), D₂O): 40.4, 53.9, 126.0, 131.9, 135.3, 137.1, 175.9

Example 16 Synthesis of n-propyl 3-amino-3-(4-bromophenyl)propionate(racemic mixtures)

To 18.0 mL (241 mmol) of n-propyl alcohol were added 4.50 g (17.2 mmol)of 3-amino-3-(4-bromophenyl)propionic acid (racemic mixtures)synthesized in Example 15 and 2.70 g (27.5 mmol) of conc. sulfuric acid,and the mixture was reacted while stirring at 55 to 60° C. for 2.5hours. At the same temperature, the solvent was removed by distillationfrom the reaction system with a predetermined amount, and the sameamount of n-propyl alcohol to that of the removed solvent was added tothe mixture and the reaction was continued. After completion of thereaction, 9 mL of water was added to the reaction mixture, and a pH ofthe mixture was adjusted to 7.4 with 6 mol/L aqueous sodium hydroxidesolution and the mixture was concentrated under reduced pressure. To theobtained concentrated residue was added 23 mL of t-butyl methyl ether,and a pH of the mixture was adjusted to 10.2 by using 6 mol/L aqueoussodium hydroxide solution. The obtained mixture was allowed to stand,liquids were separated and the organic phase was extracted and driedover anhydrous magnesium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure to give 4.93 g of n-propyl3-amino-3-(4-bromophenyl)-propionate (racemic mixtures) (isolation yieldbased on 3-amino-3-(4-bromophenyl)propionic acid (racemic mixtures):84.1%) as colorless liquid.

Incidentally, physical properties of the n-propyl3-amino-3-(4-bromophenyl)propionate (racemic mixtures) were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.91 (t, 3H, J=7.3 Hz), 1.64 (qt, 2H, 7.3, 6.8Hz), 1.71 (br, 2H), 2.63 (d, 2H, J=6.8 Hz), 4.04 (t, 2H, 6.8 Hz), 4.39(t, 2H, 6.8 Hz), 7.31 (s, 4H)

¹³C-NMR (δ (ppm), CDCl₃): 10.4, 21.9, 44.1, 52.1, 66.3, 127.7, 128.1,129.4, 131.7, 132.1171.8

MS (EI) m/z: 285, 287 (M⁺)

MS (CI, i-C₃H₁₀) m/z: 286, 288 (MH⁺)

Example 17 Syntheses of (S or R)-3-amino-3-(4-bromophenyl)propionic acidand (R or S)-n-propyl 3-amino-3-(4-bromophenyl)propionate

To a mixture comprising 0.75 mL of 50 mmol/L aqueous potassium phosphatesolution with a pH of 8.2 and 0.75 mL of t-butyl methyl ether was added300,mg (1.1 mmol) of n-propyl 3-amino-3-(4-bromophenyl)propionate acidester (racemic mixtures) synthesized in Example 16, and the mixture wasmaintained to 30° C., 15 mg of lipase (Amano Lipase PS (trade name);available from Aldrich Corporation) originated from Burkholderia cepacia(Pseudomonas cepacia) was added to the mixture at the same temperature,and the mixture was reacted while stirring at 30° C. After 5 hours, 1.0mL of acetone was added to the reaction mixture and the resultingmixture was filtered to give 113 mg of (S orR)-3-amino-3-(4-bromophenyl)propionic acid (isolation yield based onn-propyl 3-amino-3-(4-bromophenyl)propionate (racemic mixtures)=44.0%)and 12 mg of an enzyme fixing agent as a mixture. Then, liquids of thefilterate were separated, and the organic phase was extracted and driedover anhydrous magnesium sulfate, and after filtration, the filtrate wasconcentrated to give 135 mg of (R or S)-n-propyl3-amino-3-(4-bromophenyl)propionate (isolation yield based on n-propyl3-amino-3-(4-bromophenyl)propionate (racemic mixtures)=45.0%).

The (S or R)-3-amino-3-(4-bromophenyl)propionic acid was led to ann-propyl ester according to the conventional manner, and when an opticalpurity thereof was measured by using high performance liquidchromatography which uses an optically active column, it was 99.7% ee.

When an optical purity of the (R or S)-n-propyl3-amino-3-(4-bromophenyl)propionate was measured by using highperformance liquid chromatography which uses an optically active column,it was 94.0% ee.

Incidentally, the E value in the present reaction was 2779.

Analytical conditions of high performance liquid chromatography;

optically active n-propyl 3-amino-3-(4-bromophenyl)propionate

Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co., Ltd.)

Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(4-bromophenyl)propionic acid were as follows.

¹H-NMR (δ (ppm), D₂O): 2.93 (dd, 1H, J=17.1, 6.8 Hz), 3.04 (dd, 1H,J=17.1, 7.8 Hz), 4.63 (dd, 1H, J=7.8, 6.8 Hz), 7.22 (s, 1H), 7.24 (s,1H), 7.47 (s, 1H), 7.49 (s, 1H)

¹³C-NMR (δ (ppm), D₂O): 40.4, 53.9, 126.0, 131.9, 135.3, 137.1, 175.9

Physical properties of the (R or S)-n-propyl3-amino-3-(4-bromophenyl)propionate were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.91 (t, 3H, J=7.3 Hz), 1.64 (qt, 2H, 7.3,.6.8Hz), 1.71 (br, 2H), 2.63 (d, 2H, J=6.8 Hz), 4.04 (t, 2H, 6.8 Hz), 4.39(t, 2H, 6.8 Hz), 7.31 (s, 4H)

¹³C-NMR (δ (ppm), CDCl₃): 10.4, 21.9, 44.1, 52.1, 66.3, 127.7, 128.1,129.4, 131.7, 132.1171.8

MS (EI) m/z: 285, 287 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 286, 288 (MH⁺)

Comparative Example 8 Syntheses of (S orR)-3-amino-3-(4-bromophenyl)propionic acid and (R or S)-ethyl3-amino-3-(4-bromophenyl)propionate

To a mixture comprising 0.75 mL of 50 mmol/L aqueous potassium phosphatesolution with a pH of 8.2 and 0.75 mL of t-butyl methyl ether was added300 mg (1.3 mmol) of ethyl 3-amino-3-(4-bromophenyl)propionate (racemicmixtures) and the mixture was maintained to 30° C., 15 mg of lipase(Amano Lipase PS (trade name); available from Aldrich Corporation)originated from Burkholderia cepacia (Pseudomonas cepacia) was added tothe mixture at the same temperature, and the mixture was reacted whilestirring at 30° C. After 6 hours, 1.0 mL of acetone was added to thereaction mixture and the resulting mixture was filtered to give 116 mgof (S or R)-3-amino-3-(4-bromophenyl)propionic acid (isolation yieldbased on ethyl 3-amino-3-(4-bromophenyl)propionate (racemicmixtures)=43.0%) and 13 mg of an enzyme fixing agent as a mixture. Then,liquids of the filterate were separated, and the organic phase wasextracted and dried over anhydrous magnesium sulfate, and afterfiltration, the filtrate was concentrated to give 132 mg of (R orS)-ethyl 3-amino-3-(4-bromophenyl)propionate (isolation yield based onethyl 3-amino-3-(4-bromophenyl)-propionate (racemic mixtures)=44.0%).

The (S or R)-3-amino-3-(4-bromophenyl)propionic acid was led to ann-propyl ester according to the conventional manner, and when an opticalpurity thereof was measured by using high performance liquidchromatography which uses an optically active column, it was 99.4% ee.

When an optical purity of the (R or S)-ethyl3-amino-3-(4-bromophenyl)propionate was measured by using highperformance liquid chromatography which uses an optically active column,it was 95.5% ee.

Incidentally, the E value in the present reaction was 1219.

Analytical conditions of high performance liquid chromatography;

Optically active ethyl 3-amino-3-(4-bromophenyl)propionate

Optically active n-propyl 3-amino-3-(4-bromophenyl)propionate

Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co., Ltd.)

Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(4-bromophenyl)propionic acid were the same as those shownin Example 17.

Physical properties of the (R or S)-ethyl3-amino-3-(4-bromophenyl)propionate were as follows.

¹H-NMR (δ (ppm), CDCl₃): 1.23 (t, 3H, J=7.3 Hz), 1.73 (br, 2H), 2.61 (d,2H, J=6.8 Hz), 4.14 (q, 2H, 7.3 Hz), 4.39 (t, 1H, d=6.8 Hz), 7.23-7.27(m, 2H), 7.44-7.47 (m, 2H)

¹³C-NMR (δ (ppm), CDCl₃): 14.2, 44.1, 52.1, 60.6, 128.1, 131.7, 132.1,143.7, 171.7

MS (EI) m/z: 271, 273 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 272, 274 (MH⁺)

Example 18 Synthesis of 3-amino-3-(4-fluorophenyl)-propionic acid(racemic mixtures)

To 150 mL of ethanol were added 30.5 g (0.25 mol) of4-fluorobenzaldehyde, 25.6 g (0.25 mol) of malonic acid and 28.4 g (0.37mol) of ammonium acetate, and the mixture was reacted while stirringunder reflux (75 to 80° C.) for 8 hours. After completion of thereaction, the obtained reaction mixture was stirred at room temperaturefor 1 hour, filtered and dried under reduced pressure at 45° C. to give28.3 g of 3-amino-3-(4-fluorophenyl)propionic acid (racemic mixtures)(isolation yield based on 4-fluoro-benzaldehyde: 62.8%) as white powder.

Incidentally, physical properties of the3-amino-3-(4-fluorophenyl)propionic acid (racemic mixtures) were asfollows.

¹H-NMR (δ (ppm), D₂O): 2.49 (dd, 1H, J=17.1, 6.8 Hz), 2.62 (dd, 1H,J=17.1, 7.8 Hz), 4.20 (dd, 1H, J=7.8, 6.8 Hz), 6.58-6.62 (m, 2H),6.88-6.91 (s, 1H)

¹³C-NMR (δ (ppm), D₂O): 37.1, 50.5.1, 115.5, 115.8, 128.9, 130.4, 172.6

MS (EI) m/z: 183 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 184 (MH⁺)

Example 19 Synthesis of 3-amino-3-(4-fluorophenyl)-propionic acidn-propyl ester (racemic mixtures))

To 65.0 mL (870 mmol) of n-propyl alcohol were added 13.0 g (71.0 mmol)of 3-amino-3-(4-fluorophenyl)propionic acid (racemic mixtures)synthesized in Example 18 and 10.4 g (106 mmol) of conc. sulfuric acid,and the mixture was reacted while stirring at 55 to 60° C. for 2 hours.At the same temperature, the solvent was removed by distillation fromthe reaction system with a predetermined amount, and the same amount ofn-propyl alcohol to that of the removed solvent was added to the mixtureand the reaction was continued. After completion of the reaction, 20 mLof water was added to the mixture, a pH of the mixture was adjusted to7.5 with 6 mol/L aqueous sodium hydroxide solution and the mixture wasconcentrated under reduced pressure. To the obtained concentratedresidue was added 65 mL of t-butyl methyl ether, and a pH of the mixturewas adjusted to 10.2 by using 6 mol/L aqueous sodium hydroxide solution.The obtained mixture was allowed to stand, liquids were separated, theorganic phase was extracted, washed with 50 mL of saturated sodiumchloride and dried over anhydrous magnesium sulfate. After filtration,the filtrate was concentrated under reduced pressure to give 13.5 g ofn-propyl 3-amino-3-(4-fluorophenyl)propionate (racemic mixtures)(isolation yield based on 3-amino-3-(4-fluorophenyl)propionic acid(racemic mixtures): 84.6%) as colorless liquid.

Incidentally, physical properties of the n-propyl3-amino-3-(4-fluorophenyl)propionate (racemic mixtures) were as follows.

1H-NMR (δ (ppm), CDCl₃): 0.91 (t, 3H, J=7.3 Hz), 1.62 (qt, 2H, 7.3, 6.8Hz), 1.72 (br, 2H), 2.64 (d, 2H, J=6.8 Hz), 4.04 (t, 2H, 6.8 Hz), 4.42(t, 2H, 6.8 Hz), 6.99-7.04 (m, 2H), 7.32-7.35 (m, 2H)

¹³C-NMR (δ (ppm), CDCl₃): 10.3, 21.9, 44.3, 52.0, 66.2, 115.2, 115.4,127.8, 127.9, 171.9

MS (EI) m/z: 225 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 226 (MH⁺)

Example 20 Syntheses of (S or R)-3-amino-3-(4-fluorophenyl)propionicacid and (R or S)-n-propyl 3-amino-3-(4-fluorophenyl)propionate

To a mixture comprising 0.75 mL of 50 mmol/L aqueous potassium phosphatesolution with a pH of 8.2 and 0.75 mL of t-butyl methyl ether was added300 mg (1.3 mmol) of n-propyl 3-amino-3-(4-fluorophenyl)propionate(racemic mixtures) synthesized in Example 19, and the mixture wasmaintained to 30° C., 15 mg of lipase (Amano Lipase PS (trade name);available from Aldrich Corporation) originated from Burkholderia cepacia(Pseudomonas cepacia) was added to the mixture at the same temperature,and the mixture was reacted while stirring at 30° C. After 5 hours, 1.0mL of acetone was added to the reaction mixture and the resultingmixture was filtered to give 98 mg of (S orR)-3-amino-3-(4-fluorophenyl)propionic acid (isolation yield based onn-propyl 3-amino-3-(4-fluorophenyl)propionate (racemic mixtures)=40.0%)and 12 mg of an enzyme fixing agent as a mixture. Then, liquids of thefilterate were separated, and the organic phase was extracted, washedwith a saturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, and after filtration, the filtrate was concentratedto give 135 mg of (R or S)-n-propyl 3-amino-3-(4-fluorophenyl)propionate(isolation yield based on n-propyl 3-amino-3-(4-fluorophenyl)propionate(racemic mixtures)=45.0%).

The (S or R)-3-amino-3-(4-fluorophenyl)propionic acid was led to ann-propyl ester according to the conventional manner, and further led ton-propyl (S orR)-3-(2,3-dimethoxybenzoylamino)-3-(4-fluorophenyl)propionate, and whenan optical purity thereof was measured by using high performance liquidchromatography which uses an optically active column, it was 98.1% ee.

The (R or S)-n-propyl 3-amino-3-(4-fluorophenyl)propionate was led to (Ror S)-n-propyl3-(2,3-dimethoxy-benzoylamino)-3-(4-fluorophenyl)propionate and when anoptical purity thereof was measured by using high performance liquidchromatography which uses an optically active column, it was 99.4% ee.

Incidentally, the E value in the present reaction was 607.

Analytical conditions of high performance liquid chromatography;

Optically active n-propyl3-(2,3-dimethoxybenzoylamino)-3-(4-fluorophenyl)propionate,

Column: Chiralcel OJ-H (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=5/95 (volume ratio))

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(4-fluorophenyl)propionic acid were as follows.

¹H-NMR (δ (ppm), D₂O): 2.49 (dd, 1H, J=17.1, 6.8 Hz), 2.62 (dd, 1H,J=17.1, 7.8 Hz), 4.20 (dd, 1H, J=7.8, 6.8 Hz), 6.58-6.62 (m, 2H),6.88-6.91 (s, 1H)

¹³C-NMR (δ (ppm), D₂O): 37.1, 50.5.1, 115.5, 115.8, 128.9, 130.4, 172.6

MS (EI) m/z: 183 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 184 (MH⁺)

Physical properties of the (R or S)-n-propyl3-amino-3-(4-fluorophenyl)propionate were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.91 (t, 3H, J=7.3 Hz), 1.62 (qt, 2H, 7.3, 6.8Hz), 1.72 (br, 2H), 2.64 (d, 2H, J=6.8 Hz), 4.04 (t, 2H, 6.8 Hz), 4.42(t, 2H, 6.8 Hz), 6.99-7.04 (m, 2H), 7.32-7.35 (m, 2H)

¹³C-NMR (δ (ppm), CDCl₃): 10.3, 21.9, 44.3, 52.0, 66.2, 115.2, 115.4,127.8, 127.9, 171.9

MS (EI) m/z: 225 (M⁺)

MS (CI, i-C₃H₁₀) m/z: 226 (MH⁺)

Comparative Example 9 Syntheses of (S orR)-3-amino-3-(4-fluorophenyl)propionic acid and (R or S)-ethyl3-amino-3-(4-fluorophenyl)propionate

To a mixture comprising 0.75 mL of 50 mmol/L aqueous potassium phosphatesolution with a pH of 8.2 and 0.75 mL of t-butyl methyl ether was added300 mg (1.3 mmol) of ethyl 3-amino-3-(4-fluorophenyl)propionate (racemicmixtures), and the mixture was maintained to 30° C., 15 mg of lipase(Amano Lipase PS (trade name); available from Aldrich Corporation)originated from Burkholderia cepacia (Pseudomonas cepacia) was added tothe mixture at the same temperature, and the mixture was reacted whilestirring at 30° C. After 6 hours, 1.0 mL of acetone was added to thereaction mixture and the resulting mixture was filtered to give 116 mgof (S or R)-3-amino-3-(4-fluorophenyl)propionic acid (isolation yieldbased on ethyl 3-amino-3-(4-fluorophenyl)propionate (racemicmixtures)=43.0%) and 13 mg of an enzyme fixing agent as a mixture. Then,liquids of the filterate were separated, and the organic phase wasextracted and dried over anhydrous magnesium sulfate, and afterfiltration, the filtrate was concentrated to give 132 mg of (R orS)-ethyl 3-amino-3-(4-fluorophenyl)propionate (isolation yield based onethyl 3-amino-3-(4-fluorophenyl)-propionate (racemic mixtures)=44.0%).

The (S or R)-3-amino-3-(4-fluorophenyl)propionic acid was led to ann-propyl ester according to the conventional manner, and further led ton-propyl (S orR)-3-(2,3-dimethoxybenzoylamino)-3-(4-fluorophenyl)propionate, and whenan optical purity thereof was measured by using high performance liquidchromatography which uses an optically active column, it was 94.3% ee.

The (R or S)-ethyl 3-amino-3-(4-fluorophenyl)propionate was led to (R orS)-ethyl 3-(2,3-dimethoxybenzoylamino)-3-(4-fluorophenyl)propionate, andwhen an optical purity thereof was measured by using high performanceliquid chromatography which uses an optically active column, it was88.6% ee.

Incidentally, the E value in the present reaction was 101.

Analytical conditions of high performance liquid chromatography;

Optically active n-propyl3-(2,3-dimethoxybenzoylamino)-3-(4-fluorophenyl)propionate,

Optically active ethyl3-(2,3-dimethoxybenzoylamino)-3-(4-fluorophenyl)propionate

Column: Chiralcel OJ-H (0.46 cmΦ'25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=5/95 (volume ratio))

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(4-fluorophenyl)propionic acid were the same as those shownin Example 20.

Physical properties of the (R or S)-ethyl3-amino-3-(4-fluorophenyl)propionate acid ester were as follows.

¹H-NMR (δ (ppm), CDCl₃): 1.23 (t, 3H, J=7.1 Hz), 1.73 (br, 2H), 2.62 (d,2H, J=6.8 Hz), 4.13 (q, 2H7.1 Hz), 4.41 (t, 1H, d=6.8 Hz), 6.99-7.04 (m,2H), 7.32-7.35 (m, 2H)

¹³C-NMR (δ (ppm), CDCl₃): 14.2, 44.3, 52.0, 60.6, 115.3, 115.5, 127.8,127.9, 171.8

MS (EI) m/z: 211 (M⁺)

MS (CI, i-C₃H₁₀) m/z: 212 (MH⁺)

Example 21 Synthesis of 3-amino-3-(3-fluorophenyl)-propionic acid(racemic mixtures)

To 5.00 g (40.3 mmol) of 3-fluorobenzaldehyde were added 20 mL ofethanol, 4.19 g (40.3 mmol) of malonic acid and 4.66 g (60.4 mmol) ofammonium acetate, and the mixture was reacted while stirring underreflux (80 to 90)° C. for 7 hours. After completion of the reaction, theobtained reaction mixture was stirred at 0 to 5° C. for 1 hour andfiltered to give 4.27 g of 3-amino-3-(3-fluorophenyl)-propionic acid(racemic mixtures) (isolation yield based on 3-fluorobenzaldehyde:57.9%) as white powder.

Incidentally, physical properties of the3-amino-3-(3-fluorophenyl)propionic acid (racemic mixtures) were asfollows.

¹H-NMR (δ (ppm), D₂O): 2.83 (dd, 1H, J=16.1, 6.8 Hz), 2.90 (dd, 1H,J=16.1, 7.8 Hz), 4.67 (dd, 1H, J=6.8, 7.8 Hz), 7.2-7.5 (m, 5H)

¹³C-NMR (δ (ppm), D₂O): 43.4, 55.1, 116.9, 119.0, 125.7, 134.0, 141.5,164.3, 179.9

MS (EI) m/z: 183 (M⁺)

MS (CI, i-C₃H₁₀) m/z: 184 (MH⁺)

Example 22 Synthesis of n-propyl 3-amino-3-(3-fluorophenyl)propionate(racemic mixtures)

To 4.00 g (21.8 mmol) of 3-amino-3-(3-fluorophenyl)-propionic acid(racemic mixtures) synthesized in Example 21 were added 12.0 mL ofn-propyl alcohol and 3.12 g (32.8 mmol) of conc. sulfuric acid, and themixture was stirred at 55° C. for 2 hours. After 2 hours, 6 mL of avolatile material was removed under reduced pressure, 6 mL of n-propylalcohol was added to the residue, and the mixture was stirred at thesame temperature. After 1 hour, 6 mL of a volatile material was removedunder reduced pressure, 6 mL of n-propyl alcohol was added to theresidue, and the mixture was stirred at the same temperature. After 1hour, the mixture was cooled to room temperature and 8 mL of water wasadded thereto. Then, 6 mol/L aqueous sodium hydroxide solution was addedto the mixture whereby a pH of the reaction mixture was adjusted to 7.0.Under reduced pressure, a volatile material was removed, 20 mL of ethylacetate was added, and 6 mol/L aqueous sodium hydroxide solution wasadded to the mixture whereby a pH of the reaction mixture was adjustedto 8.5. The organic phase was extracted and washed with 4 mL ofsaturated brine. The obtained organic phase was dried over anhydrousmagnesium sulfate. After filtration, the filtrate was concentrated underreduced pressure to give 4.50 g of n-propyl3-amino-3-(3-fluorophenyl)propionate (racemic mixtures) (isolation yieldbased on 3-amino-3-(3-fluorophenyl)propionic acid (racemic mixtures):91.5%) as colorless liquid.

Incidentally, physical properties of the n-propyl3-amino-3-(3-fluorophenyl)propionate (racemic mixtures) were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.91 (t, 3H, J=7.3 Hz), 1.62 (tq, 2H, J=6.8,7.3 Hz), 2.63 (dd, 1H, J=5.8, 16.1 Hz), 2.67 (d, 1H, J=7.8, 16.1 Hz),4.05 (t, 2H, J=6.8 Hz), 4.42 (dd, 1H, J=5.8, 7.8 Hz), 6.9-7.3 (m, 5H)

¹³C-NMR (δ (ppm), CDCl₃): 10.3, 21.9.44.1, 52.3, 66.3, 113.3, 114.4,121.9, 130.1, 147.3, 161.8, 171.8

MS (EI) m/z: 225 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 226 (MH⁺)

Example 23 Syntheses of (S or R)-3-amino-3-(3-fluorophenyl)propionicacid and (R or S)-3-amino-3-(3-fluorophenyl)propionic acid n-propylester

To a mixture comprising 248 g (1.10 mol) of n-propyl3-amino-3-(3-fluorophenyl)propionate (racemic mixtures) synthesized inExample 22 and 620 mL of cyclohexane was added 620 mL of 50 mmol/Laqueous potassium phosphate solution with a pH of 8.2, and the mixturewas maintained to 30° C. To the obtained mixture was added 12.4 g oflipase (Amano Lipase PS (trade name); available from AldrichCorporation) originated from Burkholderia cepacia (Pseudomonas cepacia)at the same temperature, and the mixture was reacted while stirring at30° C. After 10 hours, 620 mL of cyclohexane was added to the reactionmixture, and the mixture was cooled to 12° C. To the obtained mixturewas added 201 g of sodium chloride, and the mixture was stirred at thesame temperature. After 1 hour, the mixture was filtered under reducedpressure, washed with 250 mL of cyclohexane, and dried at 45° C. underreduced pressure to give 89.9 g of (S orR)-3-amino-3-(3-fluorophenyl)propionic acid (isolation yield based onn-propyl 3-amino-3-(3-fluorophenyl)propionate (racemic mixtures)=45.0%)as white crystals, sodium chloride and an enzyme fixing agent as amixture. Also, an organic phase was extracted from the filtrate, andwashed with saturated brine, and dried over magnesium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure to give119 g of (R or S)-n-propyl 3-amino-3-(3-fluorophenyl)-propionate(isolation yield based on n-propyl 3-amino-3-(3-fluorophenyl)propionate(racemic mixtures): 48.0%) as colorless liquid.

When an optical purity of the (S orR)-3-amino-3-(3-fluorophenyl)propionic acid was measured by using highperformance liquid chromatography which uses an optically active column,it was 99.9% ee.

The (R or S)-n-propyl 3-amino-3-(3-fluorophenyl)-propionate was led to(R or S)-n-propyl 3-(4-toluoylamino)-3-(3-fluorophenyl)propionate, andwhen an optical purity thereof was measured by using high performanceliquid chromatography which uses an optically active column, it was99.9% ee.

Incidentally, the E value in the present reaction was larger than 10000.

Analytical conditions of high performance liquid chromatography;

Optically active 3-amino-3-(3-fluorophenyl)propionic acid

Column: Chiral CD-Ph (0.46 cmΦ×25 cm×2 columns connected, available fromShiseido Co., Ltd.)

Solvent: acetonitrile/water (=5/95 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Optically active n-propyl3-(4-toluoylamino)-3-(3-fluorophenyl)propionate

Column: Chiralcel OJ-H (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=5/95 (volume ratio))

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(3-fluorophenyl)propionic acid were as follows.

¹H-NMR (δ (ppm), D₂O): 2.83 (dd, 1H, J=16.1, 6.8 Hz), 2.90 (dd, 1H,J=16.1, 7.8 Hz), 4.67 (dd, 1H, J=6.8, 7.8 Hz), 7.2-7.5 (m, 5H)

¹³C-NMR (δ (ppm), D₂O): 43.4, 55.1, 116.9, 119.0, 125.7, 134.0, 141.5,164.3, 179.9

MS (EI) m/z: 183 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 184 (MH⁺)

The (S or R)-3-amino-3-(3-fluorophenyl)propionic acid was led to anethyl ester hydrochloride according to the conventional manner and aspecific rotation was measured. (S or R)-ethyl3-amino-3-(3-fluorophenyl)propionate hydrochloride: [α]²⁵ _(D)+10.70 (c1.00, H₂O)

Physical properties of the (R or S)-n-propyl3-amino-3-(3-fluorophenyl)propionate were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.91 (t, 3H, J=7.3 Hz), 1.62 (tq, 2H, J=6.8,7.3 Hz), 2.63 (dd, 1H, J=5.8, 16.1 Hz), 2.67 (d, 1H, J=7.8, 16.1 Hz),4.05 (t, 2H, J=6.8 Hz), 4.42 (dd, 1H, J=5.8, 7.8 Hz), 6.9-7.3 (m, 5H)

¹³C-NMR (δ (ppm), CDCl₃): 10.3, 21.9.44.1, 52.3, 66.3, 113.3, 114.4,121.9, 130.1, 147.3, 161.8, 171.8

MS (EI) m/z: 225 (M⁺)

MS (CI, i-C₃H₁₀) m/z: 226 (MH⁺)

Comparative Example 10 Syntheses of (S orR)-3-amino-3-(3-fluorophenyl)propionic acid and (R or S)-ethyl3-amino-3-(3-fluorophenyl)propionate

To a mixture comprising 100 mg (0.473 mmol) of ethyl3-amino-3-(3-fluorophenyl)propionate (racemic mixtures) and 250 μL ofcyclohexane was added 250 μL of 50 mmol/L aqueous potassium phosphatesolution with a pH of 8.2 and the mixture was maintained to 30° C. Tothe obtained mixture was added 5.0 mg of lipase (Amano Lipase PS (tradename); available from Aldrich Corporation) originated from Burkholderiacepacia (Pseudomonas cepacia) at the same temperature, and the mixturewas reacted while stirring at 30° C. After 5 hours, 250 μL ofcyclohexane was added to the reaction mixture, and the mixture wascooled to 12° C. To the obtained mixture was added 90 mg of sodiumchloride, and the mixture was stirred at the same temperature. After 1hour, the mixture was filtered under reduced pressure, washed with 1 mLof cyclohexane, and dried at 45° C. under reduced pressure to give 39.0mg of (S or R)-3-amino-3-(3-fluorophenyl)propionic acid (isolation yieldbased on ethyl 3-amino-3-(3-fluorophenyl)propionate (racemicmixtures)=45.0%) as white crystals, sodium chloride and an enzyme fixingagent as a mixture. Also, an organic layer was extracted from thefiltrate, washed with saturated brine, and dried over magnesium sulfate.After filtration, the filtrate was concentrated under reduced pressureto give 48.0 mg of (R or S)-ethyl 3-amino-3-(3-fluorophenyl)propionate(isolation yield based on ethyl 3-amino-3-(3-fluorophenyl)propionate(racemic mixtures): 48.0%) as colorless liquid.

When an optical purity of the (S orR)-3-amino-3-(3-fluorophenyl)propionic acid was measured by using highperformance liquid chromatography which uses an optically active column,it was 95.6% ee.

The (R or S)-ethyl 3-amino-3-(3-fluorophenyl)propionate was led to (R orS)-ethyl 3-(4-toluoylamino)-3-(3-fluorophenyl)propionate, and when anoptical purity thereof was measured by using high performance liquidchromatography which uses an optically active column, it was 95.0% ee.

Incidentally, the E value in the present reaction was 167.

Analytical conditions of high performance liquid chromatography;

Optically active 3-amino-3-(3-fluorophenyl)propionic acid

Column: Chiral CD-Ph (0.46 cmΦ×25 cm×2 columns connected, available fromShiseido Co., Ltd.)

Solvent: acetonitrile/water (=5/95 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Optically active ethyl 3-(4-toluoylamino)-3-(3-fluorophenyl)propionate

Column: Chiralcel OJ-H (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=5/95 (volume ratio))

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(3-fluorophenyl)propionic acid were the same as those shownin Example 23.

Physical properties of the (R or S)-ethyl3-amino-3-(3-fluorophenyl)propionate were as follows.

¹H-NMR (δ (ppm), CDCl₃): 1.24 (t, 3H, J=7.3 Hz), 2.61 (dd, 1H, J=7.8,16.1 Hz), 2.67 (dd, 1H, J=5.8, 16.1 Hz), 4.14 (t, 2H, J=7.3 Hz), 4.42(dd, 1H, J=5.8, 7.8 Hz), 6.9-7.3 (m, 5H)

¹³C-NMR (δ (ppm), CDCl₃): 14.2, 44.1, 52.3, 60.6, 113.3, 114.4, 121.9,130.1, 147.3, 161.8, 171.7

MS (EI) m/z: 211 (M⁺)

MS (CI, i-C₃H₁₀) m/z: 212 (MH⁺)

Example 24 Synthesis of 3-amino-3-(4-methoxyphenyl)-propionic acid(racemic mixtures)

To 150 mL of ethanol were added 28.5 g (0.21 mol) of4-methoxybenzaldehyde, 21.8 g (0.21 mol) of malonic acid and 32.3 g(0.42 mol) of ammonium acetate, and the mixture was reacted whilestirring under reflux (75 to 80° C.) for 8 hours. After completion ofthe reaction, the obtained reaction mixture was stirred at roomtemperature for 20 hours, and filtered at room temperature to give 23.6g of 3-amino-3-(4-methoxyphenyl)propionic acid (racemic mixtures)(isolation yield based on 4-methoxybenzaldehyde: 82.3%) as white powder.

Incidentally, physical properties of the3-amino-3-(4-methoxyphenyl)propionic acid (racemic mixtures) were asfollows.

¹H-NMR (δ (ppm), D₂O): 2.50 (dd, 1H, J=17.1, 6.8 Hz), 2.65 (dd, 1H,J=17.1, 7.8 Hz), 3.24 (s, 3H), 6.46 (s, 1H), 6.48 (s, 1H), 6.86 (s, 1H),6.88 (s, 1H)

¹³C-NMR (δ (ppm), D₂O): 37.1, 50.7, 55.1, 114.3, 126.9, 128.2, 159.1,172.7

MS (EI) m/z: 195 (M⁺)

MS (CI, i-C₃H₁₀) m/z: 196 (MH⁺)

Example 25 Synthesis of n-propyl 3-amino-3-(4-methoxyphenyl)propionate(racemic mixtures)

To 50.0 mL (669 mmol) of n-propyl alcohol were added 10.0 g (51.2 mmol)of 3-amino-3-(4-methoxyphenyl)propionic acid (racemic mixtures)synthesized in Example 24 and 7.50 g (76.5 mmol) of conc. sulfuric acid,and the mixture was reacted while stirring at 55 to 60° C. for 2.5hours. At the same temperature, the solvent was removed by distillationfrom the reaction system with a predetermined amount, and the sameamount of n-propyl alcohol to that of the removed solvent was added tothe mixture and the reaction was continued. After completion of thereaction, 20 mL of water was added to the reaction mixture, a pH of themixture was adjusted to 7.7 with 6 mol/L sodium hydroxide and themixture was concentrated under reduced pressure. To the obtainedconcentrated residue was added 50 mL of t-butyl methyl ether, and a pHof the mixture was adjusted to 10.0 by using 6 mol/L aqueous sodiumhydroxide solution. The obtained mixture was allowed to stand and theextracted organic phase was dried over anhydrous magnesium sulfate.After filtration, the filtrate was concentrated under reduced pressureto give 11.0 g of n-propyl 3-amino-3-(4-methoxyphenyl)propionate(racemic mixtures) (isolation yield based on3-amino-3-(4-methoxyphenyl)propionic acid (racemic mixtures): 90.5%) ascolorless liquid as colorless liquid.

Incidentally, physical properties of the3-amino-3-(4-methoxyphenyl)propionic acid n-propyl ester (racemicmixtures) were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.91 (t, 3H, J=7.3 Hz), 1.62 (qt, 2H, 7.3, 6.8Hz), 1.84 (br, 2H), 2.64 (d, 2H, J=7.3 Hz), 3.79 (s, 3H), 4.03 (t, 2H,6.8 Hz), 4.38 (t, 1H, d=7.3 Hz), 6.85 (s, 1H), 6.88 (s, 1H), 7.27 (s,1H), 7.29 (s, 1H)

¹³C-NMR (δ (ppm), CDCl₃): 10.4, 22.0, 44.3, 52.1, 55.3, 66.1, 114.0,127.3, 136.8, 158.9, 172.2

MS (EI) m/z: 237 (M⁺)

MS (CI, i-C₃H₁₀) m/z: 238 (MH⁺)

Example 26 Syntheses of (S or R)-3-amino-3-(4-methoxyphenyl)propionicacid and (R or S)-n-propyl 3-amino-3-(4-methoxyphenyl)propionate

To a mixture comprising 0.75 mL of 50 mmol/L aqueous potassium phosphatesolution with a pH of 8.2 and 0.75 mL of t-butyl methyl ether was added300 mg (1.3 mmol) of n-propyl 3-amino-3-(4-methoxyphenyl)propionate(racemic mixtures) synthesized in Example 25, and the mixture wasmaintained to 30° C., 15 mg of lipase (Amano Lipase PS (trade name);available from Aldrich Corporation) originated from Burkholderia cepacia(Pseudomonas cepacia) was added to the mixture at the same temperature,and the mixture was reacted while stirring at 30° C. After 5 hours, 1.0mL of acetone was added to the reaction mixture and the resultingmixture was filtered to give 109 mg of (S orR)-3-amino-3-(4-methoxyphenyl)propionic acid (isolation yield based onn-propyl 3-amino-3-(4-methoxyphenyl)propionate (racemic mixtures)=44.0%)and 12 mg of an enzyme fixing agent as a mixture. Then, liquids of thefilterate were separated, and the organic phase was extracted and driedover anhydrous magnesium sulfate, and after filtration, the filtrate wasconcentrated to give 135 mg of (R or S)-n-propyl3-amino-3-(4-methoxyphenyl)propionate (isolation yield based on n-propyl3-amino-3-(4-methoxyphenyl)propionate (racemic mixtures)=45.0%).

The (S or R)-3-amino-3-(4-methoxyphenyl)propionic acid was led to ann-propyl ester according to the conventional manner, and when an opticalpurity thereof was measured by using high performance liquidchromatography which uses an optically active column, it was 99.7% ee.

When an optical purity of the (R or S)-n-propyl3-amino-3-(4-methoxyphenyl)propionate was measured by using highperformance liquid chromatography which uses an optically active column,it was 98.2% ee.

Incidentally, the E value in the present reaction was 3549.

Analytical conditions of high performance liquid chromatography;

Optically active n-propyl 3-amino-3-(4-methoxyphenyl)-propionate

Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co., Ltd.)

Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(4-methoxyphenyl)propionic acid were as follows.

¹H-NMR (δ (ppm), D₂O): 2.50 (dd, 1H, J=17.1, 6.8 Hz), 2.65 (dd, 1H,J=17.1, 7.8 Hz), 3.24 (s, 3H), 6.46 (s, 1H), 6.48 (s, 1H), 6.86 (s, 1H),6.88 (s, 1H)

¹³C-NMR (δ (ppm), D₂O): 37.1, 50.7, 55.1, 114.3, 126.9, 128.2, 159.1,172.7

MS (EI) m/z: 195 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 196 (MH⁺)

Physical properties of the (R or S)-n-propyl3-amino-3-(4-methoxyphenyl)propionate were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.91 (t, 3H, J=7.3 Hz), 1.62 (qt, 2H, 7.3, 6.8Hz), 1.84 (br, 2H), 2.64 (d, 2H, J=7.3 Hz), 3.79 (s, 3H), 4.03 (t, 2H,6.8 Hz), 4.38 (t, 1H, d=7.3 Hz), 6.85 (s, 1H), 6.88 (s, 1H), 7.27 (s,1H), 7.29 (s, 1H)

¹³C-NMR (δ (ppm), CDCl₃): 10.4, 22.0, 44.3, 52.1, 55.3, 66.1, 114.0,127.3, 136.8, 158.9, 172.2

MS (EI) m/z: 237 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 238 (MH⁺)

Comparative Example 11 Syntheses of (S orR)-3-amino-3-(4-methoxyphenyl)propionic acid and (R or S)-ethyl3-amino-3-(4-methoxyphenyl)propionate)

To a mixture comprising 0.75 mL of 50 mmol/L aqueous potassium phosphatesolution with a pH of 8.2 and 0.75 mL of t-butyl methyl ether was added300 mg (1.3 mmol) of ethyl 3-amino-3-(4-methoxyphenyl)propionate(racemic mixtures), and the mixture was maintained to 30° C., 15 mg oflipase (Amano Lipase PS (trade name); available from AldrichCorporation) originated from Burkholderia cepacia (Pseudomonas cepacia)was added to the mixture at the same temperature, and the mixture wasreacted while stirring at 30° C. After 8 hours, 1.0 mL of acetone wasadded to the reaction mixture and the resulting mixture was filtered togive 106 mg of (S or R)-3-amino-3-(4-methoxyphenyl)propionic acid(isolation yield based on ethyl 3-amino-3-(4-methoxyphenyl)propionate(racemic mixtures)=43.0%) and 13 mg of an enzyme fixing agent as amixture. Then, liquids of the filterate were separated, and the organicphase was extracted and dried over anhydrous magnesium sulfate, andafter filtration, the filtrate was concentrated to give 132 mg of (R orS)-ethyl 3-amino-3-(4-methoxyphenyl)propionate (isolation yield based onethyl 3-amino-3-(4-methoxyphenyl)propionate (racemic mixtures)=44.0%).

The (S or R)-3-amino-3-(4-methoxyphenyl)propionic acid was led to ann-propyl ester according to the conventional manner, and when an opticalpurity thereof was measured by using high performance liquidchromatography which uses an optically active column, it was 98.2% ee.

When an optical purity of the (R or S)-ethyl3-amino-3-(4-methoxyphenyl)propionate was measured by using highperformance liquid chromatography which uses an optically active column,it was 97.4% ee.

Incidentally, the E value in the present reaction was 488.

Analytical conditions of high performance liquid chromatography;

Optically active n-propyl 3-amino-3-(4-methoxyphenyl)-propionate

Optically active ethyl 3-amino-3-(4-methoxyphenyl)propionate

Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co., Ltd.)

Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(4-methoxyphenyl)propionic acid were the same as thoseshown in Example 26.

Physical properties of the (R or S)-ethyl3-amino-3-(4-methoxyphenyl)propionate were as shown below.

¹H-NMR (δ (ppm), CDCl₃): 1.24 (t, 3H, J=7.3 Hz), 1.71 (br, 2H), 2.63 (d,2H, J=6.8 Hz), 3.80 (s, 3H), 4.14 (q, 2H, 7.3 Hz), 4.38 (t, 1H, d=6.8Hz), 6.86 (s, 1H), 6.88 (s, 1H), 7.27 (s, 1H), 7.29 (s, 1H)

¹³C-NMR (δ (ppm), CDCl₃): 41.3, 54.6, 104.6, 110.3, 111.9, 124.3, 132.0,150.8, 150.9, 177.3

MS (EI) m/z: 223 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 224 (MH⁺)

Example 27 Synthesis of 3-amino-3-(3,4-methylenedioxyphenyl)propionicacid (racemic mixtures)

To 100 mL of ethanol were added 20.0 g (0.13 mol) of piperonal, 13.9 g(0.13 mol) of malonic acid and 32.3 g (0.26 mol) of ammonium acetate,and the mixture was reacted while stirring under reflux (75 to 80° C.)for 15 hours. After completion of the reaction, the obtained reactionmixture was stirred at room temperature for 20 hours, and then, filteredat room temperature to give 19.5 g of3-amino-3-(3,4-methylenedioxyphenyl)propionic acid (racemic mixtures)(isolation yield based on piperonal: 70.0%) as white powder.

Incidentally, physical properties of the3-amino-3-(3,4-methylenedioxyphenyl)propionic acid (racemic mixtures)were as mentioned below.

¹H-NMR (δ (ppm), D₂O+DCl): 2.99 (dd, 2H, J=16.7, 6.8 Hz), 3.11 (dd, 1H,J=16.7, 8.1 Hz), 4.69 (dd, 1H, J=8.1, 6.8 Hz), 6.92-7.00 (m, 3H)

¹³C-NMR (δ (ppm), D₂O+DCl): 41.3, 54.6, 104.6, 110.3, 111.9, 124.3,132.0, 150.8, 150.9, 177.3

MS (EI) m/z: 209 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 210 (MH⁺)

Example 28 Synthesis of n-propyl3-amino-3-(3,4-methylenedioxyphenyl)propionate (racemic mixtures))

To 35.0 mL (468 mmol) of n-propyl alcohol were added 7.00 g (33.5 mmol)of 3-amino-3-(3,4-methylenedioxyphenyl)-propionic acid (racemicmixtures) synthesized in Example 27 and 6.60 g (67.0 mmol) of conc.sulfuric acid, and the mixture was reacted while stirring at 55 to 60°C. for 8 hours. After completion of the reaction, 14 mL of water wasadded to the reaction mixture, a pH of the mixture was adjusted to 7.5with 6 mol/L sodium hydroxide and the mixture was concentrated underreduced pressure. To the obtained concentrated residue was added 21 mLof cyclohexane, and a pH of the mixture was adjusted to 10.1 by using 6mol/L aqueous sodium hydroxide solution. The obtained mixture wasallowed to stand, and the extracted organic phase was dried overanhydrous magnesium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure to give 7.6 g of n-propyl3-amino-3-(3,4-methylenedioxyphenyl)propionate (racemic mixtures)(isolation yield based on 3-amino-3-(3,4-methylenedioxyphenyl)-propionicacid (racemic mixtures): 90.0%) as colorless liquid.

Incidentally, physical properties of the n-propyl3-amino-3-(3,4-methylenedioxyphenyl)propionate (racemic mixtures) wereas follows.

¹H-NMR (δ (ppm), CDCl₃): 0.91 (t, 3H, J=7.3 Hz) , 1.61 (qt, 2H, 7.3, 6.8Hz), 1.71 (br, 2H), 2.60 (d, 2H, J=6.8 Hz), 4.03 (t, 2H, 6.8 Hz), 4.33(t, 2H, 6.8 Hz), 6.72-6.87 (m, 3H)

MS (EI) m/z: 251 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 252 (MH⁺)

Example 29 Syntheses of (S orR)-3-amino-3-(3,4-methylenedioxyphenyl)propionic acid and (R orS)-n-propyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate)

To a mixture comprising 2.5 mL of 50 mmol/L aqueous potassium phosphatesolution with a pH of 8.2 and 2.5 mL of cyclohexane was added 1.00 g(3.98 mmol) of 3-amino-3-(3,4-methylenedioxyphenyl)propionic acidn-propyl ester (racemic mixtures) synthesized in Example 28, and themixture was maintained to 30° C., 50 mg of lipase (Amano Lipase PS(trade name); available from Aldrich Corporation) originated fromBurkholderia cepacia (Pseudomonas cepacia) was added to the mixture atthe same temperature, and the mixture was reacted while stirring at 30°C. After 5 hours, 3 mL of acetone was added to the reaction mixture andthe resulting mixture was filtered to give 350 mg of (S orR)-3-amino-3-(3,4-methylenedioxyphenyl)propionic acid (isolation yieldbased on n-propyl 3-amino-3-(3,4-methylenedioxyphenyl)-propionate(racemic mixtures)=42.0%) and 5 mg of an enzyme fixing agent as amixture. Then, liquids of the filtrate were separated, the organic phasewas extracted and dried over anhydrous magnesium sulfate, and afterfiltration, the mixture was concentrated under reduced pressure to give450 mg of (R or S)-n-propyl3-amino-3-(3,4-methylenedioxyphenyl)propionate (isolation yield based onn-propyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate (racemicmixtures)=45.0%).

The (S or R)-3-amino-3-(3,4-methylenedioxyphenyl)-propionic acid was ledto an n-propyl ester according to the conventional manner, and when anoptical purity thereof was measured by using high performance liquidchromatography which uses an optically active column, it was 99.3% ee.

When an optical purity of the (R or S)-n-propyl3-amino-3-(3,4-methylenedioxyphenyl)propionate was measured by usinghigh performance liquid chromatography which uses an optically activecolumn, it was 79.2% ee.

Incidentally, the E value in the present reaction was 752.

Analytical conditions of high performance liquid chromatography;

Optically active n-propyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate

Column: Chiral CD-Ph (0.46 cmΦ'25 cm, available from Shiseido Co., Ltd.)

Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 1.0 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(3,4-methylenedioxyphenyl)propionic acid were as follows.

¹H-NMR (δ (ppm), D₂O+DCl): 2.99 (dd, 2H, J=16.7, 6.8 Hz), 3.11 (dd, 1H,J=16.7, 8.1 Hz), 4.69 (dd, 1H, J=8.1, 6.8 Hz), 6.92-7.00 (m, 3H)

¹³C-NMR (δ (ppm), D₂O+DCl): 41.3, 54.6, 104.6, 110.3, 111.9, 124.3,132.0, 150.8, 150.9, 177.3

MS (EI) m/z: 209 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 210 (MH⁺)

Physical properties of the (R or S)-n-propyl3-amino-3-(3,4-methylenedioxyphenyl)propionate were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.91 (t, 3H, J=7.3 Hz), 1.61 (qt, 2H, 7.3, 6.8Hz), 1.71 (br, 2H), 2.60 (d, 2H, J=6.8 Hz), 4.03 (t, 2H, 6.8 Hz), 4.33(t, 2H, 6.8 Hz), 6.72-6.87 (m, 3H)

MS (EI) m/z: 251 (M⁺)

MS (CI, i-C₃H₁₀) m/z: 252 (MH⁺)

Comparative Example 12 Syntheses of (S orR)-3-amino-3-(3,4-methylenedioxyphenyl)propionic acid and (R orS)-ethyl3-amino-3-(3,4-methylenedioxyphenyl)propionate

To a mixture comprising 0.75 mL of 50 mmol/L aqueous potassium phosphatesolution with a pH of 8.2 and 0.75 mL of t-butyl methyl ether was added300 mg (1.3 mmol) of ethyl3-amino-3-(3,4-methylenedioxyphenyl)propionate (racemic mixtures), andthe mixture was maintained to 30° C., 15 mg of lipase (Amano Lipase PS(trade name); available from Aldrich Corporation) originated fromBurkholderia cepacia (Pseudomonas cepacia) was added to the mixture atthe same temperature, and the mixture was reacted while stirring at 30°C. After 15 hours, 1.0 mL of acetone was added to the reaction mixtureand the resulting mixture was filtered to give 111 mg of (S orR)-3-amino-3-(3,4-methylenedioxyphenyl)propionic acid (isolation yieldbased on ethyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate (racemicmixtures)=42.0%) and 8 mg of an enzyme fixing agent as a mixture. Then,liquids of the filterate were separated, and the organic phase wasextracted and dried over anhydrous magnesium sulfate, and afterfiltration, the filtrate was concentrated to give 132 mg of (R orS)-ethyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate (isolation yieldbased on ethyl 3-amino-3-(3,4-methylenedioxyphenyl)-propionate (racemicmixtures)=44.0%).

The (S or R)-3-amino-3-(3,4-methylenedioxyphenyl)-propionic acid was ledto an n-propyl ester according to the conventional manner, and when anoptical purity thereof was measured by using high performance liquidchromatography which uses an optically active column, it was 82.6% ee.

When an optical purity of the (R or S)-ethyl3-amino-3-(3,4-methylenedioxyphenyl)propionate was measured by usinghigh performance liquid chromatography which uses an optically activecolumn, it was 93.8% ee.

Incidentally, the E value in the present reaction was 36.

Analytical conditions of high performance liquid chromatography;

Optically active n-propyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate

Optically active ethyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate

Column: Chiral CD-Ph (0.46 cmΦ×25 cm, available from Shiseido Co., Ltd.)

Solvent: acetonitrile/water (=1/9 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 1.0 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(3,4-methylenedioxyphenyl)propionic acid were the same asthose shown in Example 29.

Physical properties of the (R or S)-ethyl3-amino-3-(3,4-methylenedioxyphenyl)propionate were as follows.

¹H-NMR (δ (ppm), CDCl₃): 1.22 (t, 3H, J=7.1 Hz), 1.73 (br, 2H), 2.58 (d,2H, J=6.8 Hz), 4.11 (q, 2H7.1 Hz), 4.31 (t, 2H, 6.8 Hz), 6.7-6.87 (m,3H)

MS (EI) m/z: 237 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 238 (MH⁺)

Comparative Example 13 Syntheses of (S orR)-3-amino-3-(4-tolyl)propionic acid and (R or S)-n-propyl3-amino-3-(4-tolyl)propionate

To a mixture comprising 500 mg (2.22 mmol) of n-propyl3-amino-3-(4-tolyl)propionate (racemic mixtures) synthesized in Example2 and 1.25 mL of cyclohexane was added 1.25 mL of water adjusted to pH8.2 with 1 mol/L aqueous potassium hydroxide solution, and the mixturewas maintained to 30° C. To the obtained mixture was added 25 mg oflipase (Amano Lipase PS (trade name); available from AldrichCorporation) originated from Burkholderia cepacia (Pseudomonas cepacia)at the same temperature, and the mixture was reacted while stirring at30° C. After 14 hours, a reaction conversion reached 49.9%.

When an optical purity of the (S or R)-3-amino-3-(4-tolyl)propionic acidwas measured by using high performance liquid chromatography which usesan optically active column, it was 98.8% ee.

The (R or S)-n-propyl 3-amino-3-(4-tolyl)propionate was led to (R orS)-n-propyl 3-(2-furoylamino)-3-(4-tolyl)-propionate, and when anoptical purity thereof was measured by using high performance liquidchromatography which uses an optically active column, it was 98.5% ee.

Incidentally, the E value in the present reaction was 837.

Analytical conditions of high performance liquid chromatography;

Optically active 3-amino-3-(4-tolyl)propionic acid

Column: Chiral CD-Ph (0.46 cmΦ×25 cm×2 columns connected, available fromShiseido Co., Ltd.)

Solvent: acetonitrile/water (=5/95 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Optically active n-propyl 3-(2-furoylamino)-3-(4-tolyl)-propionate

Column: Chiralcel OJ-H (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=1/9 (volume ratio))

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S or R)-3-amino-3-(4-tolyl)propionicacid and (R or S)-n-propyl 3-amino-3-(4-tolyl)propionate were the sameas those shown in Comparative example 5.

Comparative example 14 Syntheses of (S orR)-3-amino-3-(3-fluorophenyl)propionic acid and (R or S)-n-propyl3-amino-3-(3-fluorophenyl)propionate

To a mixture comprising 500 mg (2.22 mmol) of n-propyl3-amino-3-(3-fluorophenyl)propionate (racemic mixtures) synthesized inExample 22 and 1.25 mL of cyclohexane was added 1.25 mL of water a pH ofwhich had been adjusted to 8.2 with 1 mol/L aqueous potassium hydroxidesolution, and the mixture was maintained to 30° C. To the obtainedmixture was added 25 mg of lipase (Amano Lipase PS (trade name);available from Aldrich Corporation) originated from Burkholderia cepacia(Pseudomonas cepacia) at the same temperature, and the mixture wasreacted while stirring at 30° C. After 14 hours, a reaction conversionreached 50.0%.

When an optical purity of the (S orR)-3-amino-3-(3-fluorophenyl)propionic acid was measured by using highperformance liquid chromatography which uses an optically active column,it was 99.0% ee.

The (R or S)-n-propyl 3-amino-3-(3-fluorophenyl)-propionate was led to(R or S)-n-propyl 3-(4-toluoylamino)-3-(3-fluorophenyl)propionate, andwhen an optical purity thereof was measured by using high performanceliquid chromatography which uses an optically active column, it was98.8% ee.

Incidentally, the E value in the present reaction was 980.

Analytical conditions of high performance liquid chromatography;

Optically active 3-amino-3-(3-fluorophenyl)propionic acid

Column: Chiral CD-Ph (0.46 cmΦ×25 cm×2 columns connected, available fromShiseido Co., Ltd.)

Solvent: acetonitrile/water (=5/95 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Optically active n-propyl3-(4-toluoylamino)-3-(3-fluorophenyl)propionate

Column: Chiralcel OJ-H (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=5/95 (volume ratio))

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(3-fluorophenyl)propionic acid and (R or S)-n-propyl3-amino-3-(3-fluorophenyl)propionate were the same as those shown inExample 23.

Comparative Example 15 Syntheses of (S orR)-3-amino-3-(3-fluorophenyl)propionic acid and (R or S)-n-propyl3-amino-3-(3-fluorophenyl)propionate

To a mixture comprising 500 mg (2.22 mmol) of n-propyl3-amino-3-(3-fluorophenyl)propionate (racemic mixtures) synthesized inExample 22 and 1.25 mL of cyclohexane was added 1.25 mL of water a pH ofwhich had been adjusted to 8.2 with 1 mol/L aqueous potassium hydroxidesolution, and the mixture was maintained to 30° C. To the obtainedmixture was added 15 mg of lipase (Amano Lipase PS (trade name);available from Aldrich Corporation) originated from Burkholderia cepacia(Pseudomonas cepacia) at the same temperature, and the mixture wasreacted while stirring at 30° C. After 52 hours, a reaction conversionreached 49.2%.

When an optical purity of the (S orR)-3-amino-3-(3-fluorophenyl)propionic acid was measured by using highperformance liquid chromatography which uses an optically active column,it was 96.0% ee.

The (R or S)-n-propyl 3-amino-3-(3-fluorophenyl)propionate was led to (Ror S)-n-propyl 3-(4-toluoylamino)-3-(3-fluorophenyl)propionate, and whenan optical purity thereof was measured by using high performance liquidchromatography which uses an optically active column, it was 92.8% ee.

Incidentally, the E value in the present reaction was 167.

Analytical conditions of high performance liquid chromatography;

Optically active 3-amino-3-(3-fluorophenyl)propionic acid

Column: Chiral CD-Ph (0.46 cmΦ×25 cm×2 columns connected, available fromShiseido Co., Ltd.)

Solvent: acetonitrile/water (=5/95 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Optically active n-propyl3-(4-toluoylamino)-3-(3-fluorophenyl)propionate

Column: Chiralcel OJ-H (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=5/95 (volume ratio))

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(3-fluorophenyl)propionic acid and (R or S)-n-propyl3-amino-3-(3-fluorophenyl)propionate were the same as those shown inExample 23.

Example 30 Synthesis of n-butyl 3-amino-3-(3-fluorophenyl)propionate(racemic mixtures)

To 40.0 mL (435 mmol) of n-butyl alcohol were added 8.00 g (43.7 mmol)of 3-amino-3-(3-fluorophenyl)propionic acid (racemic mixtures)synthesized in Example 21 and 6.40 g (65.5 mmol) of conc. sulfuric acid,and the mixture was reacted while stirring at 55 to 60° C. for 3 hours.After completion of the reaction, 16 mL of water was added to thereaction mixture, a pH of the mixture was adjusted to 7.0 with 6 mol/Lsodium hydroxide and the mixture was concentrated under reducedpressure. To the obtained concentrated residue was added 40 mL ofcyclohexane, and a pH of the mixture was adjusted to 8.5 by using 6mol/L aqueous sodium hydroxide solution. The obtained mixture wasallowed to stand, liquids were separated and the extracted organic phasewas dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated under reduced pressure to give 9.40 g ofn-butyl 3-amino-3-(3-fluorophenyl)propionate (racemic mixtures)(isolation yield based on 3-amino-3-(3-fluorophenyl)propionic acid(racemic mixtures): 90%) as colorless liquid.

Incidentally, physical properties of the n-butyl3-amino-3-(3-fluorophenyl)propionate (racemic mixtures) were as follows.

¹H-NMR (δ (ppm); CDCl₃): 0.91 (t, 3H, J=7.3 Hz), 1.29-1.38 (m, 2H),1.54-1.61 (m, 2H), 1.72 (s, 2H), 2.57-2.66 (m, 2H), 4.08 (t, 2H, 6.6Hz), 4.41 (dd, 2H, J=5.9,7.8 Hz), 6.90-6.95 (m, 2H), 7.09-7.14 (m, 2H),7.25-7.30 (m, 2H)

¹³C-NMR (δ (ppm), CDCl₃): 13.68, 19.13, 30.66, 44.15, 52.34, 64.48,113.71, 121.93, 130.09, 147.57, 161.81, 164.28, 171.77

MS (EI) m/z: 239 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 240 (MH⁺)

Reference Example 4 Synthesis of isopropyl3-amino-3-(3-fluorophenyl)phenylpropionate (racemic mixtures)

To 40.0 mL (520 mmol) of isopropyl alcohol were added 8.00 g (43.7 mmol)of 3-amino-3-(3-fluorophenyl)propionic acid (racemic mixtures)synthesized in Example 21 and 6.40 g (65.5 mmol) of conc. sulfuric acid,and the mixture was reacted while stirring at 55 to 60° C. for 4 hours.After completion of the reaction, 16 mL of water was added to thereaction mixture, a pH of the mixture was adjusted to 7.0 with 6 mol/Lsodium hydroxide and the mixture was concentrated under reducedpressure. To the obtained concentrated residue was added 40 mL ofcyclohexane, and a pH of the mixture was adjusted to 8.5 by using 6mol/L aqueous sodium hydroxide solution. The obtained mixture wasallowed to stand, liquids were separated and the extracted organic phasewas dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated under reduced pressure to give 8.90 g ofisopropyl 3-amino-3-(3-fluorophenyl)propionate (racemic mixtures)(isolation yield based on 3-amino-3-(3-fluorophenyl)propionic acid(racemic mixtures): 90%) as colorless liquid.

Incidentally, physical properties of the isopropyl3-amino-3-(3-fluorophenyl)propionate (racemic mixtures) were as follows.

¹H-NMR (δ (ppm), CDCl₃): 1.19 (d, 3H, J=6.4 Hz), 1.21 (d, 3H, J=6.4 Hz),0.91 (t, 3H, J=7.3 Hz), 1.72 (s, 2H), 2.55-2.63 (m, 2H), 4.08 (t, 2H,6.6 Hz), 4.41 (dd, 2H, J=5.9, 7.8 Hz), 5.01 (qq, 1H, J=6.4,6.4 Hz),6.90-6.96 (m, 2H), 7.08-7.14 (m, 2H), 7.25-7.30 (m, 2H)

¹³C-NMR (δ (ppm), CDCl₃): 21.77, 21.80, 44.43, 44.15, 52.35, 68.00,113.71, 121.95, 130.05, 147.51, 161.77, 164.25, 171.19

MS (EI) m/z: 225 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 226 (MH⁺)

Example 31 Syntheses of (S or R)-3-amino-3-(3-fluorophenyl)propionicacid and (R or S)-n-butyl 3-amino-3-(3-fluorophenyl)propionate

To a mixture comprising 500 mg (2.22 mmol) of n-butyl3-amino-3-(3-fluorophenyl)propionate (racemic mixtures) synthesized inExample 30 and 1.25 mL of cyclohexane was added 1.25 mL of 50 mmol/Laqueous potassium phosphate solution with a pH of 8.2, and the mixturewas maintained to 30° C. To the obtained mixture was added 25 mg oflipase (Amano Lipase PS (trade name); available from AldrichCorporation) originated from Burkholderia cepacia (Pseudomonas cepacia)at the same temperature, and the mixture was reacted while stirring at30° C. After 88 hours, a reaction conversion reached 49.1%.

When an optical purity of the (S orR)-3-amino-3-(3-fluorophenyl)propionic acid was measured by using highperformance liquid chromatography which uses an optically active column,it was 99.1% ee.

The (R or S)-n-butyl 3-amino-3-(3-fluorophenyl)-propionate was led to (Ror S)-n-butyl 3-(4-toluoylamino)-3-(3-fluorophenyl)propionate, and whenan optical purity thereof was measured by using high performance liquidchromatography which uses an optically active column, it was 95.5% ee.

Incidentally, the E value in the present reaction was 842.

Analytical conditions of high performance liquid chromatography;

Optically active 3-amino-3-(3-fluorophenyl)propionic acid

Column: Chiral CD-Ph (0.46 cmΦ×25 cm×2 columns connected, available fromShiseido Co., Ltd.)

Solvent: acetonitrile/water (=5/95 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Optically active n-butyl 3-(4-toluoylamino)-3-(3-fluorophenyl)propionate

Column: Chiralcel OJ-H (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=2/98 (volume ratio))

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(3-fluorophenyl)propionic acid were the same as those shownin Example 23.

Physical properties of the (R or S)-n-butyl3-amino-3-(3-fluorophenyl)propionate were as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.91 (t, 3H, J=7.3 Hz), 1.29-1.38 (m, 2H),1.54-1.61 (m, 2H), 1.72 (s, 2H), 2.57-2.66 (m, 2H), 4.08 (t, 2H, 6.6Hz), 4.41 (dd, 2H, J=5.9,7.8 Hz), 6.90-6.95 (m, 2H), 7.09-7.14 (m, 2H),7.25-7.30 (m, 2H)

¹³C-NMR (δ (ppm), CDCl₃): 13.68, 19.13, 30.66, 44.15, 52.34, 64.48,113.71, 121.93, 130.09, 147.57, 161.81, 164.28, 171.77

MS (EI) m/z: 239 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 240 (MH⁺)

Comparative Example 16 Syntheses of (S orR)-3-amino-3-(3-fluorophenyl)propionic acid and isopropyl (R orS)-3-amino-3-(3-fluorophenyl)propionate

To a mixture comprising 500 mg (2.22 mmol) of isopropyl3-amino-3-(3-fluorophenyl)propionate (racemic mixtures) synthesized inReference example 4 and 1.25 mL of cyclohexane was added 1.25 mL of 50mmol/L aqueous potassium phosphate solution with a pH of 8.2, and themixture was maintained to 30° C. To the obtained mixture was added 25 mgof lipase (Amano Lipase PS (trade name); available from AldrichCorporation) originated from Burkholderia cepacia (Pseudomonas cepacia)at the same temperature, and the mixture was reacted while stirring at30° C. After 88 hours, a reaction conversion reached 18.1%.

When an optical purity of the (S orR)-3-amino-3-(3-fluorophenyl)propionic acid was measured by using highperformance liquid chromatography which uses an optically active column,it was 98.1% ee.

The isopropyl (R or S)-3-amino-3-(3-fluorophenyl)-propionate was led toisopropyl (R or S)-3-(4-toluoyl-amino)-3-(3-fluorophenyl)propionate, andwhen an optical purity thereof was measured by using high performanceliquid chromatography which uses an optically active column, it was21.7% ee.

Incidentally, the E value in the present reaction was 128.

Analytical conditions of high performance liquid chromatography;

Optically active 3-amino-3-(3-fluorophenyl)propionic acid

Column: Chiral CD-Ph (0.46 cmΦ×25 cm×2 columns connected, available fromShiseido Co., Ltd.)

Solvent: acetonitrile/water (=5/95 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Optically active isopropyl3-(4-toluoylamino)-3-(3-fluorophenyl)propionate

Column: Chiralcel OJ-H (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=2/98 (volume ratio))

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(3-fluorophenyl)propionic acid were the same as those shownin Example 23.

Physical properties of the isopropyl (R orS)-3-amino-3-(3-fluorophenyl)propionate were as follows.

¹H-NMR (δ (ppm), CDCl₃): 1.19 (d, 3H, J=6.4 Hz) , 1.21 (d, 3H, J=6.4Hz), 0.91 (t, 3H, J=7.3 Hz), 1.72 (s, 2H), 2.55-2.63 (m, 2H), 4.08 (t,2H, 6.6 Hz), 4.41 (dd, 2H, J=5.9, 7.8 Hz), 5.01 (qq, 1H, J=6.4,6.4 Hz),6.90-6.96 (m, 2H), 7.08-7.14 (m, 2H), 7.25-7.30 (m, 2H)

¹³C-NMR (δ (ppm), CDCl₃): 21.77, 21.80, 44.43, 44.15, 52.35, 68.00,113.71, 121.95, 130.05, 147.51, 161.77, 164.25, 171.19

MS (EI) m/z: 225 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 226 (MH⁺)

Reference Example 5 Synthesis of s-butyl3-amino-3-(3-fluorophenyl)propionate

To 60.0 mL (649 mmol) of s-butyl alcohol were added 6.00 g (32.8 mmol)of 3-amino-3-(3-fluorophenyl)propionic acid (racemic mixtures)synthesized in Example 21 and 4.80 g (49.1 mmol) of conc. sulfuric acid,and the mixture was reacted while stirring at 55 to 60° C. for 3 hours.After completion of the reaction, 12 mL of water was added to thereaction mixture, a pH of the mixture was adjusted to 7.0 with 6 mol/Lsodium hydroxide and the mixture was concentrated under reducedpressure. To the obtained concentrated residue was added 30 mL ofcyclohexane, and a pH of the mixture was adjusted to 8.5 by using 6mol/L aqueous sodium hydroxide solution. The obtained mixture wasallowed to stand, liquids were separated and the extracted organic phasewas dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated under reduced pressure to give 5.50 g ofs-butyl 3-amino-3-(3-fluorophenyl)propionate (isolation yield based on3-amino-3-(3-fluorophenyl)propionic acid (racemic mixtures): 70%) ascolorless liquid.

Incidentally, physical properties of the s-butyl3-amino-3-(3-fluorophenyl)propionate were as follows.

“Diastereomer Mixture”

¹H-NMR (δ (ppm), CDCl₃): 0.83-0.89 (m, 3H), 1.16-1.65 (m, 3H), 1.46-1.65(m, 1H), 1.71 (s, 2H), 2.58-2.68 (m, 2H), 4.42 (dd, 1H, J=6.4, 13.7 Hz),4.82-4.99 (m, 1H), 6.97-7.33 (m, 1H), 7.09-7.15 (m, 1H), 7.23-7.33 (m,1H)

MS (EI) m/z: 239 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 240 (MH⁺)

Comparative Example 17 Syntheses of (S orR)-3-amino-3-(3-fluorophenyl)propionic acid and s-butyl (3R or3S)-3-amino-3-(3-fluorophenyl)propionate

To a mixture comprising 500 mg (2.09 mmol) of s-butyl3-amino-3-(3-fluorophenyl)propionate synthesized in Reference example 5and 1.25 mL of cyclohexane was added 1.25 mL of 50 mmol/L aqueouspotassium phosphate solution with a pH of 8.2, and the mixture wasmaintained to 30° C. To the obtained mixture was added 25 mg of lipase(Amano Lipase PS (trade name); available from Aldrich Corporation)originated from Burkholderia cepacia (Pseudomonas cepacia) at the sametemperature, and the mixture was reacted while stirring at 30° C. After60 hours, a reaction conversion reached 21.7%.

When an optical purity of the (S orR)-3-amino-3-(3-fluorophenyl)propionic acid was measured by using highperformance liquid chromatography which uses an optically active column,it was 99.0% ee.

Analytical conditions of high performance liquid chromatography;

Optically active 3-amino-3-(3-fluorophenyl)propionic acid Column: ChiralCD-Ph (0.46 cmΦ×25 cm×2 columns connected, available from Shiseido Co.,Ltd.)

Solvent: acetonitrile/water (=5/95 (volume ratio))

Potassium dihydrogen phosphate 40 mmol/L

Adjusted to pH 3.5 with phosphoric acid

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S orR)-3-amino-3-(3-fluorophenyl)propionic acid were the same as those shownin Example 23.

Physical properties of the s-butyl (3R or3S)-3-amino-3-(3-fluorophenyl)propionate were as follows.

“Diastereomer Mixture”

¹H-NMR (δ(ppm), CDCl₃): 0.83-0.89 (m, 3H), 1.16-1.65 (m, 3H), 1.46-1.65(m, 1H), 1.71 (s, 2H), 2.58-2.68 (m, 2H), 4.42 (dd, 1H, J=6.4, 13.7 Hz),4.82-4.99 (m, 1H), 6.97-7.33 (m, 1H), 7.09-7.15 (m, 1H), 7.23-7.33 (m,1H)

MS (EI) m/z: 239 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 240 (MH⁺)

Comparative Example 18 Syntheses of (S)-3-amino-3-phenylpropionic acidand (R)-n-propyl 3-amino-3-phenylpropionate

To a mixture comprising 500 mg (2.41 mmol) of n-propyl3-amino-3-phenylpropionate (racemic mixtures) synthesized in Referenceexample 2 and 1.25 mL of cyclohexane was added 1.25 mL of water a pH ofwhich had been adjusted to 8.2 with 1 mol/L aqueous potassium hydroxidesolution, and the mixture was maintained to 30° C. To the obtainedmixture was added 25 mg of lipase (Amano Lipase PS (trade name);available from Aldrich Corporation) originated from Burkholderia cepacia(Pseudomonas cepacia) at the same temperature, and the mixture wasreacted while stirring at 30° C. After 26 hours, a reaction conversionreached 42.6%.

The (R)-n-propyl 3-amino-3-phenylpropionate was led to (R)-n-propyl3-(2-furoylamino)-3-phenylpropionate, and when an optical purity thereofwas measured by using high performance liquid chromatography which usesan optically active column, it was 73.4% ee.

Incidentally, the E value in the present reaction was 441.

Analytical conditions of high performance liquid chromatography:

optically active 3-(2-furoylamino)-3-phenylpropionic acid n-propyl ester

Column: Chiralcel OJ-H (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=1/9 (volume ratio))

Flow rate: 0.5 mL/min

Temperatrure: 30° C.

Wavelength: 220 nm

Also, physical properties of the (S)-3-amino-3-phenylpropionic acid and(R)-n-propyl 3-amino-3-phenylpropionate were the same as those shown inExample 1.

Utilizability in Industry

According to the present invention, a novel n-alkyl3-amino-3-arylpropionate can be provided with a high yield and a simpleand easy process and a process for preparing the same can be provided.

Also, according to the present invention, an Industrially suitableprocess for preparing an optically active 3-amino-3-arylpropionic acidand an optically active n-alkyl 3-amino-3-arylpropionate can be providedby a simple and easy process which gives an optically active (S orR)-3-amino-3-arylpropionic acid and an optically active (R or S)-n-alkyl3-amino-3-arylpropionate simultaneously from 3-amino-3-arylpropionicacid ester (racemic mixtures) with high E values.

1. An n-alkyl 3-amino-3-arylpropionate represented by the formula (I):

wherein Ar¹ represents an aryl group which may have a substituent(s),provided that a phenyl group and 4-methoxyphenyl group are excluded, R¹represents an n-propyl group or an n-butyl group.
 2. An (R or S)-n-alkyl3-amino-3-arylpropionate represented by the formula (I-a):

wherein Ar¹ and R¹ have the same meanings as defined in claim 1, and *represents an asymmetric carbon.
 3. A process for preparing an n-alkyl3-amino-3-arylpropionate represented by the formula (IV):

wherein R¹ represents an n-propyl group or an n-butyl group, and Arrepresents an aryl group which may have a substituent(s), provided thata phenyl gruop is excluded, which comprises (A) a first step of reactingan arylaldehyde represented by the formula (II):

wherein Ar has the same meaning as defined above, and malonic acid andammonium acetate in an organic solvent to make a 3-amino-3-arylpropionicacid represented by the formula (III):

wherein Ar has the same meaning as defined above, (B) then, a secondstep fo reacting the resulting compound with a 3-amino-3-arylpropionicacid and n-propyl alcohol or n-butyl alcohol in the presence of an acidcatalyst.
 4. The process for preparing an n-alkyl3-amino-3-arylpropionate according to claim 3, wherein the organicsolvent is an alcohol solvent.
 5. The process for preparing an n-alkyl3-amino-3-arylpropionate according to claim 4, wherein the alcoholsolvent is ethanol or isopropyl alcohol.
 6. A process for preparing anoptically active (S or R)-3-amino-3-arylpropionic acid represented bythe formula (III-a):

wherein Ar represents an aryl group which may have a substituent(s),and * represents an asymmetric carbon, and an optically active (R orS)-n-alkyl 3-amino-3-arylpropionate represented by the formula (IV-a):

wherein Ar and * have the same meanings as defined above, and R¹represents an n-propyl group or an n-butyl group, provided that it has areverse absolute configuration to that of the compound of the formula(III-a), which comprises subjecting either one of enantiomers of n-alkyl3-amino-3-arylpropionate which is racemic mixtures and represented bythe formula (IV):

wherein Ar and R¹ have the same meanings as defined above, toselectively hydrolysis reaction in the presence of a hydrolase in amixed solvent of an organic solvent and a buffer.
 7. The processaccording to claim 6, wherein the hydrolase is protease, esterase orlipase.
 8. The process according to claim 6, wherein the hydrolase islipase originated from Burkholderia cepacia (Pseudomonas cepacia). 9.The process according to claim 6, wherein the organic solvent is analiphatic hydrocarbon, an aromatic hydrocarbon or an ether, or a mixedsolvent of the above.
 10. The process according to claim 6, wherein theorganic solvent is cyclohexane, t-butyl methyl ether or toluene.
 11. Theprocess according to claim 6, wherein the buffer is at least oneselected from the group consisting of an aqueous sodium phosphatesolution, an aqueous potassium phosphate solution, an aqueous sodiumacetate solution, an aqueous sodium citrate solution and an aqueousammonium acetate solution.
 12. The process according to claim 6, whereinthe buffer is at least one selected from the group consisting of anaqueous sodium phosphate solution and an aqueous potassium phosphatesolution.
 13. The process according to claim 11, wherein a concentrationof the buffer is 0.05 to 0.5 mol/L.
 14. The process according to claim6, wherein the hydrolysis reaction is carried out at 10 to 50° C. 15.The process according to claim 6, wherein the hydrolysis reaction iscarried out at 30 to 45° C.
 16. The process according to claim 6,wherein each of the optically active (S or R)-3-amino-3-arylpropionicacid represented by the formula (III-a):

wherein Ar has the same meaning as defined above, and * represents anasymmetric carbon, and the optically active (R or S)-n-alkyl3-amino-3-arylpropionate represented by the formula (IV-a):

wherein Ar and R¹ have the same meanings as defined above, * representsan asymmetric carbon, provided that it has a reverse absoluteconfiguration to the compound of the formula (III-a), formed by thehydrolysis reaction is isolated from the mixture thereof.
 17. Theprocess according to claim 6, wherein Ar is a phenyl group, 2-tolylgroup, 3-tolyl group, 4-tolyl group, 2,3-xylyl group, 2-chlorophenylgroup, 3-chlorophenyl group, 4-chlorophenyl group, 2,3-dichlorophenylgroup, 2,4-dichlorophenyl group, 3,4-dichlorophenyl group,3,5-dichlorophenyl group, 2-bromophenyl group, 3-bromophenyl group,4-bromophenyl group, 2-fluorophenyl group, 3-fluorophenyl group,4-fluorophenyl group, 3,4-difluorophenyl group, 2-iodophenyl group,3-iodophenyl group, 4-iodophenyl group, 2-methoxyphenyl group,3-methoxyphenyl group, 4-methoxyphenyl group, 2,3-dimethoxyphenyl group,3,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group or3,4-methylenedioxyphenyl group.
 18. The process according to claim 7,wherein the hydrolase is lipase originated from Burkholderia cepacia(Pseudomonas cepacia).
 19. The process according to claim 12, wherein aconcentration of the buffer is 0.05 to 0.5 mol/L.
 20. The processaccording to claim 16, wherein Ar is a phenyl group, 2-tolyl group,3-tolyl group, 4-tolyl group, 2,3-xylyl group, 2-chlorophenyl group,3-chlorophenyl group, 4-chlorophenyl group, 2,3-dichlorophenyl group,2,4-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenylgroup, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group,2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group,3,4-difluorophenyl group, 2-iodophenyl group, 3-iodophenyl group,4-iodophenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group,4-methoxyphenyl group, 2,3-dimethoxyphenyl group, 3,4-dimethoxyphenylgroup, 3,5-dimethoxyphenyl group or 3,4-methylenedioxyphenyl group.